Ni-Catalyzed Dual C-H Annulation of Benzimidazoles with Alkynes for Synthesis of π-Extended Heteroarenes

Article abstract of DOI:10.1021/acs.orglett.1c01253

Transition metal catalyzed dual C-H activation and annulation with alkynes was an attractive protocol to construct polycyclic π-extended structures. However, most of them were dominated by noble metal catalysts. Disclosed herein was the study of base-metal Ni-catalysis for dual C-H annulation of N-aromatic imidazole, which produced a range of desired polycyclic aza-quinolines in 48-95% yields. The use of bifunctional phosphine oxide ligand proved to be critical for success.

Full text of DOI:10.1021/acs.orglett.1c01253

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Letter
Ni-Catalyzed Dual C−H Annulation of Benzimidazoles with Alkynes
for Synthesis of π‑Extended Heteroarenes
Shao-Long Qi, Yue Li, Jiang-Fei Li, Tao Zhang, Yu-Xin Luan,* and Mengchun Ye*
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ABSTRACT: Transition metal catalyzed dual C−H activation and annulation with
alkynes was an attractive protocol to construct polycyclic π-extended structures. However,
most of them were dominated by noble metal catalysts. Disclosed herein was the study of
base-metal Ni-catalysis for dual C−H annulation of N-aromatic imidazole, which produced
a range of desired polycyclic aza-quinolines in 48−95% yields. The use of bifunctional
phosphine oxide ligand proved to be critical for success.
a
Scheme 2. Condition Optimization
olycyclic π-extended heteroaromatic structures are prev-
Palent scaffolds in both medicinal and material chemistry,
because they often featured remarkable biological, optical, and
electronic properties.1 The development of efficient methods
for their synthesis has thus become an important topic and
attracted much attention. Although diverse methods have been
explored, most of them focused on classical reactions starting
with prefunctionalized substrates2 (Scheme 1a, left). The
prefunctionalization required lengthy synthetic procedures,
hence decreasing the overall efficiency. By contrast, transition-
metal-catalyzed direct dual C−H activation and annulation
Scheme 1. Synthesis of Polycyclic π-Extended Structures
a
Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), Ni(cod)2 (10
mol %), ligand (10 mol %), AlMe3 (60 mol %), toluene (0.5 mL) at
b
1
80 °C for 12 h, and yield was determined by H NMR. All ratios
c
refer to 1H NMR yield (%) of 3a/3a′. AlMe3 (80 mol %) and 2a (0.6
mmol). Ar1 = 2,6-iPr2C6H3, Ar2 = 2,4,6-Me3C6H2, Ar3 = 3,5-tBu2C6H3.
with alkynes emerged as a more attractive alternative, because
it allowed one-step construction of cyclic scaffolds from
widespread C−H bonds,3 thus leading to increasing atom and
step economy (Scheme 1a, right). In 2009, by using Pd(OAc)2
as the catalyst, the Jiao group4 demonstrated a cyclo-
Received: April 13, 2021
Published: May 10, 2021
https://doi.org/10.1021/acs.orglett.1c01253
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4034−4039
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Scheme 3. Scope of N-Aromatic Benzimidazoles
Scheme 4. Scope of Alkynes
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), Ni(cod)2 (10
mol %), L13 (10 mol %), AlMe3 (80 mol %), toluene (0.5 mL); yield
for isolated products.
catalysts. In consideration of the low abundance in the earth’s
crust and the high cost of Rh and Pd metals, noble metal
catalysis compromised the sustainability of these protocols. In
addition, metal oxidants are required to regenerate catalysts in
most cases, resulting in low atom economy.
Given the cost-effective and sustainable nature, the develop-
ment of base metal-catalyzed dual C−H annulations to access
such extended π-systems was regarded as a more environ-
mentally benign and economically attractive alternative.14
Recently, nickel catalysis gained increasing attention owing
to its unique catalytic reactivity and low cost. However, nickel-
catalyzed dual C−H annulations for the synthesis of π-
extended polyheterocycles have not been achieved yet, which
might be ascribed to the following reasons: (1) a large excess
of heteroatoms in substrates could coordinate with nickel
species, leading to catalyst deactivation; (2) most of reported
Ni-catalyzed C−H activation reactions are limited to specific
substrates that contain acidic C−H bonds or bidentate
directing groups,15 while nonacidic C−H bonds without a
bidentate directing group are still quite challenging. To address
these challenges, we envisioned using a distinctive bimetallic
catalytic system to explore such reactions, hoping to enhance
interaction between the target C−H bond and Ni catalyst by
forming cyclic intermediates as well as suppress coordinating
deactivation of Ni. Herein, we report our result, in which a
bifunctional phosphine oxide (PO)16 ligand enabled a Ni−Al
bimetallic catalysis17,18 for dual C−H annulation of N-aromatic
imidazoles with alkynes, offering a variety of aza-quinolines in
48−95% yields (Scheme 1c).
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), Ni(cod)2 (10
mol %), L13 (10 mol %), AlMe3 (80 mol %), toluene (0.5 mL); yield
for isolated products.
aromatization of arylindoles with alkynes via dual C−H
activation, achieving various polycyclic carbazoles. Later in
2011, Miura and co-workers5 reported a [Cp*RhCl2]2-
catalyzed oxidative coupling of phenylazoles with alkynes
with Cu(OAc)2·H2O as oxidant. With the same or modified
Rh catalysts, a variety of polycyclic heteroaromatic compounds
were prepared via dual C−H annulations by the Miura,6
Chen,7 Li,8 Wang,9 Choudhury,10 You,11 and Punniyamru-
thy12,13 groups (Scheme 1b). Despite great progress, these
reported systems have been dominated by noble metal
Considering the broad utility of imidazole scaffolds, N-
phenyl benzimidazole (1a) and dec-5-yne (2a) were selected
as model substrates to commence our initial studies. Results
revealed that common carbene and phosphine ligands were
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ineffective, affording only C2-alkenylated byproduct 3a′
(Scheme 2, L1−L3). Then secondary phosphine oxide
Ph2P(O)H was tested, but only a trace amount of product
3a was detected (L4). Considering the vital influence of the
steric and electronic property of ligand substituents on the
catalytic activity, diverse phosphine oxides were optimized.
Pleasingly, when Cy2P(O)H L5 was used, desired product 3a
was produced in a yield of 14%. Albeit in low yield, this result
demonstrated the successful Ni-catalysis for the target
annulation. By switching the backbone from a secondary
phosphine oxide to a diamino-phosphine oxide, L6 led to an
increased yield of 30%. Then substituent screening revealed
that di-tert-butylethyldiamino phosphine oxide L8 offered a
higher yield of 52%, but aromatic substituted ligands provided
no annulation product at all (L9−L10). Notably, cyclohexanedi-
amine-derived ligands exhibited better performance (L11−L15)
and a yield of 66% was obtained (L13). Then, increasing the
loading of alkyne and AlMe3 afforded a 93% yield, and in this
case only a trace amount of byproduct 3a′ was detected. It is
worth noting that, with low-valent Ni species as the catalyst,
trimerization of alkyne was observed as well, and the amount
of benzene derivative byproduct varied with reaction
conditions, with the yield being 9% under optimized
conditions. Control experiments showed that removal of any
component from the combination of Ni, Al, and L13 led to no
product, suggesting the critical role of the PO-bound Ni−Al
bimetallic catalyst.
Scheme 5. Mechanistic Experiments and a Plausible
Mechanism
With the above-mentioned optimal reaction conditions
established, we turned to investigate the substrate scope with
respect to imidazole substrates (Scheme 3). Imidazoles with
electron-rich or electron-poor substituents on the N-aromatic
ring all were competent substrates, offering aza-quinolines in
58%−95% yields (3b−3n). Functional groups including Me,
t
Et, Bu, OMe, OCF3, Ph, and CF3 were all well tolerated.
Scheme 6. Optical Property of the aza-Quinolines: (a)
Fluoresence Emission Spectra in CH2Cl2 Solution; (b)
Fluorescence Images of aza-Quinolines in Both the Solid
State and CH2Cl2 Solution under UV Light
Notably, satisfactory yields were retained in the presence of
ester group CO2Et, demonstrating the elegant recognition
ability of Al to the N atom of imidazole (3k, 3l). When the C3-
substituted N-aromatic ring was employed, C6−H activation
occurred due to steric hindrance (3c, 3d, 3h, 3l, 3n). And
substrates with C3-electron-donating groups generally pro-
vided higher yields, which suggested an electrophilic C−H
activation mechanism (3c, 3d, 3h). Besides, the pattern of
benzimidazole proved to be versatile as well. Benzimidazoles
decorated with different substituents all participated in the
annulation smoothly (3o−3u). Higher yields were observed
for electron-rich substrates compared with electron-poor ones,
likely due to the enhanced coordination ability to Al, which in
turn promoted the C−H activation of the imidazole ring (3p
vs 3u). Yields decreased with C4 or C7 substituted
benzimidazoles, probably because increased steric hindrance
impeded the second C−H activation step (3o, 3t).
Next, the compatibility of alkynes with this annulation
reaction was examined. As shown in Scheme 4, reactions took
place readily with a set of alkynes. Excellent yields ranging from
83% to 91% were observed for alkynes containing different
alkyl groups such as Et, nPr, and nhexyl (4a−4e). When
nonsymmetric alkyne was subjected to the standard conditions,
nearly 1:1 mixtures were furnished (4d, 4e). Aromatic alkynes
bearing H, Me, or Et were competent partners as well,
delivering desired products smoothly though in moderate
yields (4f−4i). Trimethyl(prop-1-yn-1-yl)silane was also tested
as protected terminal alkyne but gave no desired product.
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To gain insight into the reaction mechanism, some
mechanistic experiments were performed. Reaction with 1a-d
under standard conditions showed that D was transferred into
the alkene byproduct (Scheme 5a, eq 1), suggesting the dual
role of alkyne as both coupling partner and hydrogen acceptor,
which explained the requirement for excess alkynes. No
significant kinetic isotopic effect was observed for the C2−H of
imidazole (kH/kD = 1.02) (Scheme 5a, eq 2) and the C−H of
phenyl ring (kH/kD = 1.04) (Scheme 5a, eq 3), indicating that
the cleavage of both C−H bonds could not be involved in the
rate-determining step. An intramolecular competitive experi-
ment with 1a-d′ gave a kH/kD value of 3.76 (Scheme 5a, eq 4),
demonstrating the second C−H activation was irreversible.
In consideration of the fact that excess AlMe3 had little
influence on the total yield of 3a and 3a′, but changed the ratio
of 3a and 3a′ (see Table S3 and S12), excess AlMe3 might
accelerate the second C−H bond activation. We reasoned that
excess AlMe3 might coordinate to the imidazole, thus releasing
Al-Lewis acid of the Al−O−P−Ni catalyst from the imidazole
and forming a ring-opened intermediate, which would allow
the second C−H bond activation to proceed more easily. On
the basis of these observations and previous discusstions,18c,d,19
a plausible mechanism was proposed as shown in Scheme 5b.
First, the in situ generated PO-bound Ni−Al bimetallic
complex docked at the N atom of imidazole (A), acting as a
directing group to deliver Ni to the target C−H bond. Then
imidazole C−H bond cleavage took place through oxidative
addition followed by alkyne insertion or direct ligand to ligand
H-transfer20 with the alkyne to generate C. The following
aromatic C(sp2)−H activation resulted in intermediate D.
Subsequent alkyne insertion and reductive elimination formed
aza-quinoline and regenerated the catalyst.
To demonstrate their potential application as optical
material, the photophysical property of aza-quinolines was
then investigated. We characterized six representative com-
pounds in solution at room temperature and in the solid state
(powders), and the emission spectra were depicted as shown in
Scheme 6. Generally, all these π-conjugated systems exhibited
interesting optical properties. In addition, incorporation of
electron-donating groups led to red shifts of the photo-
luminescence maxima compared with electron-withdrawing
ones (3p vs 3u, 3g vs 3m). Decoration on the N-aromatic ring
has more significant influence on the optical property in
contrast with the benzimidazole ring (3m vs 3u). Notably,
introduction of aromatic rings by using aromatic alkynes
resulted in a further prominent red shift (4i).
AUTHOR INFORMATION
Corresponding Authors
■
Yu-Xin Luan − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0001-5364-4895; Email: yxluan@nankai.edu.cn
Mengchun Ye − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0002-2019-5365; Email: mcye@nankai.edu.cn
Authors
Shao-Long Qi − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Yue Li − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Jiang-Fei Li − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Tao Zhang − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01253
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(91856104, 21871145), the Tianjin Applied Basic Research
Project and Cutting-Edge Technology Research Plan
(19JCZDJC37900), and the Fundamental Research Funds
for the Central Universities (63191601) for financial support.
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In summary, we have successfully developed a ligand-
enabled base metal Ni-catalyzed method to access π-
conjugated polycyclic heteroaromatic molecules via C−H
activation of N-aromatic benzimidazole and annulation with
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