Practical Synthesis of Benzimidazo[1,2- A[quinolines via Rh(III)-Catalyzed C-H Activation Cascade Reaction from Imidamides and Anthranils

Article abstract of DOI:10.1021/acs.orglett.9b04256

We report a novel and practical one-pot Rh(III)-catalyzed strategy to construct benzimidazo[1,2-a]quinolines from readily available imidamides and anthranils. The cascade reaction proceeds via a C-H amination-cyclization-cyclization process in ionic liquid without any additives and possesses simple operation, moderate-to-high yield, and broad substrate scope features, which will provide the reference for the construction of biologically active fused benzimidazoles.

Full text of DOI:10.1021/acs.orglett.9b04256

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Practical Synthesis of Benzimidazo[1,2‑a]quinolines via Rh(III)-
Catalyzed C−H Activation Cascade Reaction from Imidamides and
Anthranils
Yao Hu, Ting Wang, Yanzhao Liu, Ruifang Nie, Ninghong Yang, Qiantao Wang, Guo-Bo Li,*
and Yong Wu*
Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
S
* Supporting Information
ABSTRACT: We report a novel and practical one-pot
Rh(III)-catalyzed strategy to construct benzimidazo[1,2-
a]quinolines from readily available imidamides and anthranils.
The cascade reaction proceeds via a C−H amination−
cyclization−cyclization process in ionic liquid without any
additives and possesses simple operation, moderate-to-high
yield, and broad substrate scope features, which will provide
the reference for the construction of biologically active fused
benzimidazoles.
Imidamides are well-known precursors for the construction
enzimidazo[1,2-a]quinolines are a class of important
Bfunctionalized units bearing a variety of bioactive of benzimidazoles with coupling reagents that can provide N
sources.13 Considering the peculiarity of anthranils (exposing
properties, such as antitumor, antiviral, antifungal, antibacte-
carbonyl group after breaking the N−O bond)14 and our
previous work on the C−H activation of imidamides,15 we
reasoned that benzimidazo[1,2-a]quinolines may be prepared
from imidamides and anthranils via C−H activation/
annulation, followed by intramolecular Knoevenagel con-
densation under certain conditions. After several attempts,
we obtained an efficient Rh(III)-catalyzed C−H activation/
annulation cascade reaction to synthesize benzimidazo[1,2-
a]quinolines starting from imidamides and anthranils in an
ionic liquid (IL) (Scheme 1c). This transformation could
proceed smoothly under air in the absence of extra additives.
Control experiments have shown that the metal catalyst was
unnecessary for the intramolecular Knoevenagel condensation
process.
We selected N-(p-tolyl)acetimidamide (1a) and 5-chloro-3-
phenylbenzo[c]isoxazole (2a) as the model substrates (Table
1). To our delight, when [Cp*RhCl2]2, AgSbF6, and PivOH
were used at 120 °C in MeCN, the target product 3aa was
gained in 15% yield (entry 1). Whereafter, the effect of other
traditional solvents was investigated (entries 2−4; other
solvents are displayed in Table S1). The results showed that
MeOH gave an increased yield to 42%, whereas other
traditional solvents, like H2O, EtOH, THF, 1,4-dioxane,
DMF, and DCE, were incompatible with this cascade reaction.
ILs with a series of advantages including low volatility, high
thermal/chemical stability, and a wide electrochemical
rial, and many others.1 The synthetic methods for
benzimidazo[1,2-a]quinolines hence have received much
attentions. To the best of our knowledge, the previous
methods mostly employed 2-amino quinolines or benzimida-
zoles as the starting materials (Scheme 1a). Initially, 2-
aminoquinoline and trinitrophenol were used to synthesize
unsubstituted benzimidazo[1,2-a]quinolines.2 Later, substi-
tuted benzimidazo[1,2-a]quinolines were prepared from
quinolines by palladium catalysis,3 copper(II) catalysis,4 or
hypervalent iodine(III) catalysis.5 In addition, two methods
have been established by employing benzimidazoles as the
substrates: One was started with the intermolecular Knoeve-
nagel condensation, followed by photochemical dehydrocycli-
zation,1a,6 Cu-catalyzed Ullmann-type coupling,7 or an SNAr
reaction,8 and the other underwent a cascade of N-arylation−
intramolecular Knoevenagel condensation.9 Usually, these
traditional methods were limited by multistep syntheses or
low yield, especially the restrictive starting materials. Recently,
transition-metal-catalyzed C−H activation was extensively
explored as an effective tool to extend heterocyclic scaffolds.10
In this respect, two strategies have been established for
synthesizing benzimidazole-fused quinolines based on
rhodium(III)-catalyzed11 and palladium-catalyzed12 C−H
activation (Scheme 1b), which both employed benzimidazoles
with specific functional groups as the starting materials,
probably limiting their synthetic applications. In this regard,
the exploration of a new methodology to construct the
benzimidazo[1,2-a]quinoline unit starting from more easily
available materials is currently desirable.
Received: November 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04256
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
we then tried several ILs as the solvents (entries 5−8).
Surprisingly, [BMIM]BF4 (1-butyl-3-methylimidazolium tetra-
fluoroborate) was suitable for this transformation, affording the
desired product in 71% yield (entry 5). As the temperature
increased, the yield of 3aa increased (entries 9−11) and
achieved 82% at 140 °C. Interestingly, no obvious differences
were observed in the reaction efficiency and yields when
removing AgSbF6 or PivOH (entries 12 and 13). Screening of
different catalysts revealed that [Cp*IrCl2]2 was also a
somewhat effective catalyst (entry 14), whereas the others
were not suitable for this transformation (entries 15 and 16).
After the optimal conditions were obtained, the scope and
generality of N-arylimidamides (1a−y) with 5-chloro-3-
phenylbenzo[c]isoxazole 2a was investigated (Scheme 2). N-
Scheme 1. Synthesis of Benzimidazo[1,2-a]quinoline
a
Scheme 2. Scope of N-Arylimidamides
a
Table 1. Optimization for Rh-Catalyzed Cascade Reaction
b
entry
additives
solvent
MeCN
H2O
EtOH
MeOH
[BMIM]BF4
[BMIM]OTf
[BMIM]NTf2
[BMIM]OAc
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
temp. (°C) yield (%)
1
2
3
4
5
6
7
8
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6/PivOH
AgSbF6
120
120
120
120
120
120
120
120
130
140
150
140
140
140
140
140
15
0
a
Reaction conditions: 1 (0.10 mmol), 2a (0.12 mmol), catalyst (5
mol %), and solvent (0.6 mL), 140 °C for 24 h under air. Isolated
trace
42
71
66
52
0
78
82
80
85
84
78
0
b
yields. 1.0 mmol scale reaction.
Phenylacetimidamides with various electron-donor or -accept-
or groups at the para position of the phenyl moiety reacted
well with 2a to gain the corresponding products (3aa−ga, 46−
84%).
9
The strong electron-withdrawing group NO2 at the para
position substantially affected the reaction (3ha). Interestingly,
the yields of the derivatives with Cl (3ja) or Br (3ka)
substituted on the para position were markedly lower than that
of the F-substituted derivative 3ia, possibly implying that
halogenated N-phenylacetimidamides had a great influence on
the reactivity. A substituent group at the o- or m-position of N-
phenylacetimidamide was suitable for this transformation as
well, and the C−H activation would happen at the o-position
of less steric hindrance (3la−oa). However, introducing F into
the meta position yielded an unseparated mixture with an
approximately 3:2 ratio of o-position to o′-position (3pa, the
ratio is elucidated from 1H NMR). The imidamide bearing two
substitutes on the phenyl moiety could be processed to provide
the relevant product 3qa in 73% yield. N-(4-(1H-Pyrazol-1-
yl)phenyl)acetimidamide and N-(naphthalen-1-yl)-
10
11
12
13
c
14
15
16
d
e
21
a
Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), catalyst (5
mol %), AgSbF6 (20 mol %), PivOH (1.0 equiv), solvent (0.6 mL), 24
b
c
h under air. Isolated yields. [Cp*IrCl2]2 was used as a catalyst.
d
e
[Ru(p-cymene)Cl2]2 was used as a catalyst. Cp*Co(CO)I2 was
used as a catalyst.
window, are considered as better substitutes to traditional
solvents in organic chemistry.16 On the basis of our previous
studies for developing ILs as the C−H activation platform,17
B
DOI: 10.1021/acs.orglett.9b04256
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acetimidamide also reacted well with 2a to generate 3ra and
3sa in good yield. Besides this, the cascade reaction could be
extensively used for other N-phenylalkylimidamides (1t−x),
giving the expected products (3ta−xa) in good to excellent
yield (64−89%). When employing N-(p-tolyl)benzimidamide
as the substrate, only the corresponding benzimidazole (3ya)
was found, probably due to the blocking of intramolecular
Knoevenagel condensation in the absence of α-H of the N−H
imine group. When enlarging 1a to a 1.0 mmol scale, 3aa was
obtained in 54% yield.
Scheme 4. Mechanistic Studies
Next, a series of 2,1-benzisoxazoles were researched under
the standard conditions. As shown in Scheme 3, the 3-aryl-
a
Scheme 3. Scope of Anthranils
competition experiment was conducted to afford a ratio of
4aa and 4ia in 4.5:1, suggesting that the electron-rich arene is
in favor (Scheme 4d).
On the basis of these mechanistic experiments and the
reported literature,10h,13,14e,17a,18 a plausible mechanism for this
reaction is displayed in Scheme 5. The active complex A might
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1a (0.10 mmol), 2 (0.12 mmol), catalyst (5
mol %), and solvent (0.6 mL), 140 °C for 24 h under air. Isolated
yields.
benzo[c]isoxazoles with different substituents on the phenyl
moiety at the three-position of the anthranil unit were
successfully reacted with 1a to afford 5-aryl benzimidazo[1,2-
a]quinolines (3ab−ae, 67−87%). Variations of other groups
such as H, Me, or Br at the five-position of the anthranil ring
were also compatible (3af−ah, 59−83%). In addition,
unsubstituted anthranil coupled to 1a could also generate the
isolated 3ai in 68% yield.
Then, the mechanism of the cascade reaction was explored
(Scheme 4). The control experiments of 1a and 2a were
performed in 30 min under standard conditions, and the
intermediate 4aa was found as the main product. After treating
4aa only in [BMIM]BF4 at 140 °C for 12 h, the yield of 3aa
was up to 91% (Scheme 4a), indicating that the cascade
reaction was carried out via the intermediate 4aa, and a metal
catalyst was unnecessary for the intramolecular Knoevenagel
condensation. The subsequent hydrogen−deuterium exchange
experiment of 1a was investigated in [BMIM]BF4/CD3OD (v/
v 9:1), and 15% D at the ortho site of the phenyl unit was
observed, suggesting that the rupture of the ortho C−H bond
was reversible (Scheme 4b). The kinetic isotope effect (KIE)
experiment revealed a value (KH/KD) of 0.98 from two parallel
groups, indicated that the break of the C−H bond was
probably not in the turnover-limiting process (Scheme 4c). To
test the electronic preference of this transformation, a
be generated by exchanging the anion of [Cp*RhCl2]2 and
[BMIM]BF4. Then, 1a coordinates to complex A, and the
ortho C−H bond of the phenyl moiety is cleaved to give the
six-membered rhodacycle B. Anthranil 2a coordinates to B,
and the subsequent ring opening produces the intermediate C
with the exposure of the carbonyl group. The amino group is
supposed to migrate and insert into the C−Rh bond to provide
D. Then, the migration insertion of the Rh−N (2a) bond into
the CN bond furnishes the amide complex E, which
removes one molecule of A and NH3 to form the intermediate
4aa. Ultimately, the 3aa is obtained from the intramolecular
Knoevenagel condensation of 4aa at high temperature.
In summary, an efficient and practical Rh(III)-catalyzed C−
H activation/annulation cascade reaction was established to
C
DOI: 10.1021/acs.orglett.9b04256
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Liang, D.; He, Y.; Liu, L.; Zhu, Q. Org. Lett. 2013, 15, 3476−
3479.
(6) Hranjec, M.; Karminski-Zamola, G. Molecules 2007, 12, 1817−
1828.
(7) (a) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding, K. Org.
Lett. 2010, 12, 1500−1503. (b) Jin, H.; Zhou, B.; Gao, J.; Jiang, D.;
Jia, J.; Yang, Z. Synthesis 2010, 2010, 2794−2798.
(8) Han, S.; Jiang, Z.; Miao, D.; Tong, Y.; Pan, Q.; Li, X.; Hu, R.
Synthesis 2015, 47, 1913−1921.
construct benzimidazo[1,2-a]quinolines in [BMIM]BF4 with-
out extra additives. This methodology is characterized by easily
obtained materials, a broad substrate scope, simple operation,
and moderate to high yield. It will be a useful strategy to
prepare benzimidazo[1,2-a]quinoline based bioactive mole-
cules. Further exploration for other studies of imidamides and
anthranils is underway in our lab.
ASSOCIATED CONTENT
* Supporting Information
(9) (a) Kato, J.; Ito, Y.; Ijuin, R.; Aoyama, H.; Yokomatsu, T. Org.
Lett. 2013, 15, 3794−3797. (b) da Silva, R. B.; Lange Coelho, F.;
Rodembusch, F. S.; Schwab, R. S.; Schneider, J. M. F. M.; da Silveira
Rampon, R.; Schneider, P. H. New J. Chem. 2019, 43, 11596−11603.
(c) Nagesh, H. N.; Suresh, A.; Reddy, M. N.; Suresh, N.;
Subbalakshmi, J. G.; Chandra Sekhar, K. V. G. RSC Adv. 2016, 6,
15884−15894.
(10) (a) Ge, Q.; Li, B.; Wang, B. Org. Biomol. Chem. 2016, 14,
1814−1821. (b) Shi, L.; Wang, B. Org. Lett. 2016, 18, 2820−2823.
(c) Villar, J. M.; Suarez, J.; Varela, J. A.; Saa, C. Org. Lett. 2017, 19,
1702−1705. (d) Cheng, J.; Yang, R.; Wu, X.; Sun, S.; Yu, J. Synthesis
2018, 50, 3487−3492. (e) Dhole, S.; Sun, C. Adv. Synth. Catal. 2019,
361, 535−541. (f) Liu, J.; Fang, H.; Cheng, R.; Wang, Z.; Yang, Y.;
You, J. Chem. Commun. 2019, 55, 7097−7100. (g) Xiao, Y.; Wu, X.;
Wang, H.; Sun, S.; Yu, J. T.; Cheng, J. Org. Lett. 2019, 21, 2565−
2568. (h) Biswas, A.; Sarkar, S.; Samanta, R. Chem. - Eur. J. 2019, 25,
3000−3004.
(11) (a) Huang, J.; Dong, L.; Han, B.; Peng, C.; Chen, Y. Chem. -
Eur. J. 2012, 18, 8896−8900. (b) Ghorai, D.; Choudhury, J. Chem.
Commun. 2014, 50, 15159−15162. (c) Ge, Q.; Li, B.; Song, H.;
Wang, B. Org. Biomol. Chem. 2015, 13, 7695−7710. (d) Wezeman, T.;
Scopelliti, R.; Tirani, F. F.; Severin, K. Adv. Synth. Catal. 2019, 361,
1383−1388.
(12) Li, X.; Chen, X.; Wang, H.; Chen, C.; Sun, P.; Mo, B.; Peng, J.
Org. Biomol. Chem. 2019, 17, 4014−4023.
(13) (a) Xu, L.; Wang, L.; Feng, Y.; Li, Y.; Yang, L.; Cui, X. Org. Lett.
2017, 19, 4343−4346. (b) Li, Y.; Jia, C.; Li, H.; Xu, L.; Wang, L.; Cui,
X. Org. Lett. 2018, 20, 4930−4933. (c) Huang, S.; Li, H.; Sun, X.; Xu,
L.; Wang, L.; Cui, X. Org. Lett. 2019, 21, 5570−5574.
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04256.
Detailed description of experiment procedures, charac-
terization data and spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wyong@scu.edu.cn (Y.W.).
*E-mail: liguobo@scu.edu.cn (G.-B.L).
ORCID
Qiantao Wang: 0000-0002-5553-6246
Guo-Bo Li: 0000-0002-4915-6677
Yong Wu: 0000-0003-0719-4963
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the support from the National Natural
Science Foundation of China (grant nos. 81373259 and
81573286).
(14) (a) Yu, S.; Tang, G.; Li, Y.; Zhou, X.; Lan, Y.; Li, X. Angew.
Chem., Int. Ed. 2016, 55, 8696−700. (b) Li, L.; Wang, H.; Yu, S.;
Yang, X.; Li, X. Org. Lett. 2016, 18, 3662−3665. (c) Mishra, N. K.;
Jeon, M.; Oh, Y.; Jo, H.; Park, J.; Han, S.; Sharma, S.; Han, S. H.;
Jung, Y. H.; Kim, I. S. Org. Chem. Front. 2017, 4, 241−249. (d) Kim,
S.; Han, S. H.; Mishra, N. K.; Chun, R.; Jung, Y. H.; Kim, H. S.; Park,
J. S.; Kim, I. S. Org. Lett. 2018, 20, 4010−4014. (e) Wang, M.; Kong,
L.; Wang, F.; Li, X. Adv. Synth. Catal. 2017, 359, 4411−4416.
(15) Lai, R.; Wu, X.; Lv, S.; Zhang, C.; He, M.; Chen, Y.; Wang, Q.;
Hai, L.; Wu, Y. Chem. Commun. 2019, 55, 4039−4042.
(16) (a) Dai, C.; Zhang, J.; Huang, C.; Lei, Z. Chem. Rev. 2017, 117,
6929−6983. (b) Greaves, T. L.; Drummond, C. J. Chem. Rev. 2008,
108, 206−237.
(17) (a) Liu, Y.; Hu, Y.; Lv, G.; Nie, R.; Peng, Y.; Zhang, C.; Lv, S.;
Hai, L.; Wang, H.; Wu, Y. ACS Sustainable Chem. Eng. 2019, 7,
13425−13429. (b) Lv, S.; Li, Y.; Yao, T.; Yu, X.; Zhang, C.; Hai, L.;
Wu, Y. Org. Lett. 2018, 20, 4994−4997. (c) Ma, Q.; Yu, X.; Lai, R.;
Lv, S.; Dai, W.; Zhang, C.; Wang, X.; Wang, Q.; Wu, Y. ChemSusChem
2018, 11, 3672−3678. (d) Zhang, C.; Chen, X.; Luo, Y.; Li, J.; Chen,
M.; Hai, L.; Wu, Y. ACS Sustainable Chem. Eng. 2018, 6, 13473−
13479.
(18) (a) Yu, S.; Li, Y.; Zhou, X.; Wang, H.; Kong, L.; Li, X. Org. Lett.
2016, 18, 2812−2815. (b) Jeon, M.; Park, J.; Dey, P.; Oh, Y.; Oh, H.;
Han, S.; Um, S. H.; Kim, H. S.; Mishra, N. K.; Kim, I. S. Adv. Synth.
Catal. 2017, 359, 3471−3478. (c) Zeng, Z.; Jin, H.; Sekine, K.;
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed.
2018, 57, 6935−6939. (d) Wu, X.; Xiao, Y.; Sun, S.; Yu, J. T.; Cheng,
J. Org. Lett. 2019, 21, 6653−6657. (e) Yao, T.; Du, K. ACS
Sustainable Chem. Eng. 2019, 7, 6068−6077. (f) Li, Y.; Qi, Z.; Wang,
H.; Yang, X.; Li, X. Angew. Chem., Int. Ed. 2016, 55, 11877−11881.
REFERENCES
■
̌
́
(1) (a) Hranjec, M.; Kralj, M.; Piantanida, I.; Sedic, M.; Suman, L.;
́
Pavelic, K.; Karminski-Zamola, G. J. Med. Chem. 2007, 50, 5696−
5711. (b) Sedic, M.; Poznic, M.; Gehrig, P.; Scott, M.; Schlapbach, R.;
Hranjec, M.; Karminski-Zamola, G.; Pavelic, K.; Pavelic, S. K. Mol.
Cancer Ther. 2008, 7, 2121−2132. (c) Perin, N.; Uzelac, L.;
Piantanida, I.; Karminski-Zamola, G.; Kralj, M.; Hranjec, M. Bioorg.
Med. Chem. 2011, 19, 6329−6339. (d) Brajsa, K.; Vujasinovic, I.; Jelic,
D.; Trzun, M.; Zlatar, I.; Karminski-Zamola, G.; Hranjec, M. J. J.
́
Enzyme Inhib. Med. Chem. 2016, 31, 1139−1145. (e) Perin, N.; Alic,
J.; Liekens, S.; Van Aerschot, A.; Vervaeke, P.; Gadakh, B.; Hranjec,
M. New J. Chem. 2018, 42, 7096−7104. (f) Hranjec, M.; Pavlovic, G.;
Marjanovic, M.; Kralj, M.; Karminski-Zamola, G. Eur. J. Med. Chem.
2010, 45, 2405−17. (g) Perin, N.; Nhili, R.; Cindric, M.; Bertosa, B.;
Vusak, D.; Martin-Kleiner, I.; Laine, W.; Karminski-Zamola, G.; Kralj,
M.; David-Cordonnier, M. H.; Hranjec, M. Eur. J. Med. Chem. 2016,
122, 530−545. (h) Perin, N.; Martin-Kleiner, I.; Nhili, R.; Laine, W.;
David-Cordonnier, M. H.; Vugrek, O.; Karminski-Zamola, G.; Kralj,
M.; Hranjec, M. MedChemComm 2013, 4, 1537−1550.
(2) Morgan, G.; Stewart, J. J. Chem. Soc. 1938, 1292−1305.
(3) Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org.
Chem. 2006, 71, 1280−1283.
(4) (a) Rasheed, S.; Rao, D. N.; Das, P. J. Org. Chem. 2015, 80,
9321−7. (b) Masters, K. S.; Rauws, T. R.; Yadav, A. K.; Herrebout,
W. A.; Van der Veken, B.; Maes, B. U. Chem. - Eur. J. 2011, 17, 6315−
6320. (c) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am.
Chem. Soc. 2010, 132, 13217−13219.
(5) (a) He, Y.; Huang, J.; Liang, D.; Liu, L.; Zhu, Q. Chem. Commun.
2013, 49, 7352−7354. (b) Rao, D. N.; Rasheed, S.; Vishwakarma, R.
A.; Das, P. RSC Adv. 2014, 4, 25600−25604. (c) Manna, S.; Matcha,
K.; Antonchick, A. P. Angew. Chem., Int. Ed. 2014, 53, 8163−8166.
D
DOI: 10.1021/acs.orglett.9b04256
Org. Lett. XXXX, XXX, XXX−XXX