Synthesis of Benzodiazepines Through Ring Opening/Ring Closure of Benzimidazole Salts

Article abstract of DOI:10.1002/chem.201905828

Pyrido-benzodiazepine derivatives are undoubtedly one of the most important structural motifs in the marketed drugs and the drug candidates. Commonly synthetic methods for construction of the benzodiazepine ring derivatives are based on the condensation reactions of two highly functionalized synthons. The development of synthesis for these compounds, however, is hampered by the regioselectivity and atom economy. In this work, a one-step synthesis of pyrido-benzodiazepine backbones and its analogues is achieved through continuous ring-opening hydrolysis of benzimidazole salts and intramolecular C?H bond activation. The reaction mechanism is explored by control experiments and density functional theory (DFT) calculations.

Full text of DOI:10.1002/chem.201905828

A Journal of
Accepted Article
Title: Synthesis of Benzodiazepines via Ring Opening/
Ring Closure of Benzimidazole Salts
Authors: Sheng Tao, Qingqing Bu, Qianqian Shi, Donghui Wei, Bin
Dai, and Ning Liu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201905828
Link to VoR: http://dx.doi.org/10.1002/chem.201905828
Supported by

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
Synthesis of Benzodiazepines via Ring Opening/Ring Closure of
Benzimidazole Salts
Sheng Tao,[a] Qingqing Bu,[a] Qianqian Shi,[b] Donghui Wei,*[b] Bin Dai,*[a] and Ning Liu*[a]
further being N-functionalization (Scheme 2, pathway 1). To
overcome above disadvantage in pathway 1 caused by ortho-
phenyldiamine, various coupling partners, such as ortho-
Abstract: Pyrido-benzodiazepine derivatives are undoubtedly one of
the most important structural motifs in the marketed drugs and the
drug candidates. Commonly synthetic methods for construction of the
benzodiazepine ring derivatives are based on the condensation
reactions of two highly functionalized synthons. The development of
synthesis for these compounds, however, is hampered by the
regioselectivity and atom economy. In this work, a one-step synthesis
of pyrido-benzodiazepine backbones and its analogues is achieved
through continuous ring-opening hydrolysis of benzimidazole salts
and intramolecular C−H bond activation. The reaction mechanism is
explored by the control experiments and density functional theory
calculations (DFT) method.
nitroaniline,[12]
2-chloropyridin-3-amine,[13]
2-aminobenzoic
acid,[14] methyl 2-aminobenzoate,[15] 2-bromobenzamide,[16] as
well as three-components system,[17] have been used to displace
the ortho-phenyldiamine for the synthesis of pyrido-
benzodiazepine compounds, with a focus on achieving high
selectivity (Scheme 2, pathway 2).
Introduction
Pyrido-benzodiazepine derivatives are ubiquitous structural core
of many synthesized molecules with widespread applications in
clinical medicines.[1] In particular, benzo- and pyridino-diazepine
compounds are important heterocyclic derivatives used
extensively in pharmaceutical application.[2] For example, various
benzo- and pyrido-benzodiazepine derivatives find important
uses in several marketed pharmaceuticals, such as BI-RJ-70,[3]
Scheme 1. Scaffolds of pyrido-benzodiazepine compounds.
Nuvenzepine,[4]
Clozapine,[5]
BRS-3,[6]
Nevirapine,[7]
Propizepine,[8] and Pirenzepine[9] (Scheme 1). Consequently, the
development of methods for the synthesis of pyrido-
benzodiazepine compounds is important in medicinal chemistry
and represents a worthwhile goal for organic synthesis.[10]
Commonly synthetic methods for construction of pyrido-
benzodiazepine derivatives are based on the condensation
reactions of two highly functionalized synthons (Scheme 2,
pathways 1 and 2). A most frequently used approach is the
condensation of substituted ortho-phenyldiamine with 2-
Despite replacing of starting materials could achieve a significant
improvement in selectivity, the wide, atom-economic and
sustainable application of current developed method is hindered
by the need for the multistep sequences, and/or the employment
of N-protecting groups. Although synthetic strategies for synthesis
of benzodiazepine ring derivatives have been widely explored, it
is highly desirable to improve the atom- and step-economy as well
as high selectivity. We envisioned a new and powerful method to
address this need.
chloronicotinic
acid
to
achieve
pyrido-benzodiazepine
compounds.[6, 9b, 11] However, this method led to a regioisomeric
mixture of products due to poor regioselectivity of two NH2 of
benzene ring is difficult to control (Scheme 2, pathway 1).[6a, 12] In
addition, the aforementioned resulting products also suffered from
poor site selectivity at two NH with pyrido-benzodiazepine for
In our previous work, we have developed a synthetic method for
the unsymmetrical pyridine-bridged pincer-type imidazolium
salts,[18] which have shown to be effective organocatalysts.[19]
Moreover, metal-based catalysts[20] by coordinating with
unsymmetrical ligands have been successfully used in the
cycloaddition of epoxides with CO2 and the Suzuki coupling
reaction.[21] During the preparing of the metal-catalysts, we
discovered that the benzimidazole salts can hydrolyze to form the
ring opened products (Scheme 3, the first step),[21] this result was
met with other groups’.[22] Recently, direct C−H bond activation
have emerged as an efficient and powerful strategy toward
complex molecules construction with high atom- and step-
economy.[23] Success in C−H bond activation made it possible
based on the ring opened hydrolysis products to seven-
membered diazepine ring, which established a powerful new
synthetic tool at the C3 position of pyridine ring (Scheme 3, the
second step). In this article, we report a straightforward and atom-
economical strategy for construction of pyrido-benzodiazepine
[a]
[b]
S. Tao, Dr. Q. Bu, Prof. Dr. B. Dai, Dr. N. Liu
School of Chemistry and Chemical Engineering, Key Laboratory for
Green Processing of Chemical Engineering of Xinjiang Bingtuan
Shihezi University
450001 Shihezi (China)
E-mail: ningliu@shzu.edu.cn; ninglau@163.com; dbinly@126.com
Prof. Dr. D. Wei, Qianqian Shi
College of Chemistry, Center of Computational Chemistry
Zhengzhou University
450001 Zhengzhou (China)
E-mail: donghuiwei@zzu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
derivatives through continuous ring-opening hydrolysis of
benzimidazole salts and intramolecular C−H bond activation.
system for this reaction. As expected, increasing reaction
temperature was favorable toward product formation. The yields
of product increased from 63% to 76% when reaction temperature
increased from 60 ºC to 70 ºC (Table 1, entries 5 vs 6). The
loading amount of Ag2CO3 is crucial for the transformation and a
3 equiv. Ag2CO3 exhibits the best result (Table 1, entries 6-9). It
is noteworthy that the operation procedure has an obvious effect
on the reaction transformation (Table 1, entries 6 vs 11). 1a and
Ag2CO3 stirred in THF at room temperature for 2 h is required to
acquire high conversion. After this, heating reaction mixtures to
reflux for 22 h afforded the desired product 2a.
Table 1. Optimization of reaction conditions.[a]
Entry
Silver salts (mmol)
T (°C)
Time (h)
Yield (%)
1
Ag2O (1.5)
60
60
60
60
60
70
70
70
70
rt
2+22[b]
2+22[b]
2+22[b]
2+22[b]
2+22[b]
2+22[b]
2+22[b]
2+22[b]
2+22[b]
2+22[b]
24[c]
24
2
AgF (1.5)
NR
NR
NR
63
3
AgPF6 (1.5)
AgNO3 (1.5)
Ag2CO3 (1.5)
Ag2CO3 (1.5)
Ag2CO3 (2.0)
Ag2CO3 (1.0)
Ag2CO3 (0.5)
Ag2CO3 (1.5)
Ag2CO3 (1.5)
4
Scheme 2. Strategies for the construction of pyrido-
benzodiazepine.
5
6
76
7
79
8
59
9
21
10
11
NR
54
Scheme 3. Cut and sew strategy for the construction of pyrido-
benzodiazepine derivatives.
70
[a] Reaction conditions: benzimidazole iodine salt 1a (0.5 mmol),
silver salt (1.5 mmol), THF (tetrahydrofuran, 2 ml). [b] the reaction
was first stirred for 2 h at room temperature and then heated to
reflux (60 or 70 °C) for 22 h. [c] The reaction was directly heated
to reflux for 24 h.
Results and Discussion
In order to identify a suitable catalyst system, as well as suitable
reaction conditions, we started our investigation to synthesize
benzodiazepine ring derivatives via continuous ring-opening
hydrolysis and intramolecular C−H bond activation of
benzimidazole salts 1a. Silver salts, including Ag2O, AgF, AgPF6,
AgNO3, and Ag2CO3 were screened, and Ag2CO3 showed the
best performance (Table 1, entry 5). Ag2O was also able to
promote this reaction (Table 1, entry 1); however, it displayed
much lower performance than Ag2CO3. Other silver salts hardly
showed any activity (Table 1, entries 2-4). After screening the
solvents (see Table S1 in the Supporting Information), it was
found that Ag2CO3 combined with THF was a high effective
With the optimized reaction conditions in hand, the scope of the
benzimidazole iodine salt for synthesis of the benzodiazepine ring
compounds was investigated in Table 2. The effect of substituents
of quaternary ammonium cations were first investigated under the
optimized reaction conditions. The aliphatic substituents of
quaternary ammonium salts, such as methyl, n-propyl, i-propyl, n-
butyl, benzyl, phenylpropyl, and allyl group, proceeded smoothly
to generate the desired benzodiazepine ring products in moderate
to good yields (Table 2, 2a-g). Single crystal X-ray diffraction
analysis of 2b and 2f were consistent with the desired products
This article is protected by copyright. All rights reserved.

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
structure, confirming the predicted structures of the pyrido-
benzodiazepine products. The electron nature of substituents at
the ortho-position to the pyridine ring was explored using N-propyl
substituted substrates. It was found that various substituents at
pyridine ring both electron-neutral and electron-donating group,
such as fluoro, bromo, chloro, cyano, acetyl, trifluoromethyl,
methyl, pyrazolyl, indazolyl, methoxy, and morpholino group,
were suitable for construction of benzodiazepine ring derivatives
through continuous ring-opening hydrolysis of benzimidazole
salts and intramolecular C−H bond activation, giving the desired
products in moderate to excellent yields (Table 2, 2h-r). The
molecular structure of 2p was confirmed by X-ray crystallography.
This reaction system tolerated different substituents at meta- and
para-position to the pyridine ring. This affords the desired
products with 65-87% yield (Table 2, 2s-y).
Table 2. Scope of substrates.[a]
[a] Reaction conditions: benzimidazole iodine salt 1a (0.5 mmol),
Ag2CO3 (1.5 mmol), THF (tetrahydrofuran, 2 ml), the reaction was
first stirred for 2 h at room temperature and then heated to reflux
(70 °C) for 22 h.
Encouraged by these promising results aforementioned, we next
proceeded to evaluate N-heteroaryl substituted substrates (Table
3). As showed in Table 3, two N-heteroaryl substituted quaternary
ammonium salts, such as quinoline and pyrazine, could smoothly
afford the pyrido-benzodiazepine products in a high yield of 82%
(Table 3, 3a) and 71% (Table 3, 3b), respectively. The effect of
substituents of benzimidazole were also explored under the
optimized reaction conditions. It was found that benzimidazole
with a wide range of functional groups such as methyl, ester, nitro,
bromo, chloro, and methoxy were tolerated and moderate to good
yields of products were obtained (Table 3, 3c-k). When substrates
such as substituents at 8- or 9-position to benzene ring were
employed, the phenomenon of the existence of isomers is usually
observed. It was found that the electronic effect of substituents at
8- or 9-position to benzene ring for the selectivity of products was
This article is protected by copyright. All rights reserved.

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
shown to be remarkable. In the presence of electron-withdrawing
group such as ester and nitro group, the benzodiazepine ring
products 3d and 3e were isolated in good yields with the exclusive
regioselectivity at 8-position to benzene ring. Unexpectedly,
substrates of halogenated substituents such as bromo and chloro
group, produced 3f-i in 8- or 9-substituted mixture products.
Delightedly, the resulting 8- or 9-substituted mixture products
were easy to separate and gave 8- and 9-halogenated products,
respectively. The structures of 3h (chloro group at 8-position) and
3i (chloro group at 9-position) were confirmed by the X-ray
crystallography.
result indicates that the radical pathway may be not involved in
this transformation. As indicated in Scheme 4, no kinetic isotope
effect (KIE ≈ 1) was obtained, suggesting that C-H bond cleavage
at C-3 position to pyridine ring is not the rate-limiting step,
(Scheme 4, b), which agrees with the calculated results (Figure
1). Control experiments (Scheme 4, c) indicates that a ring-
opening product is formed via hydrolysis of benzimidazole salts,
which further occurred an intramolecular C−H bond activation,
resulting in the benzodiazepine ring product 2a.
Table 3. Scope of nitrogen heterocycles.[a]
[a] Reaction conditions: benzimidazole iodine salt 1a (0.5 mmol),
Ag2CO3 (1.5 mmol), THF (tetrahydrofuran, 2 ml), the reaction was
first stirred for 2 h at room temperature and then heated to reflux
(70 °C) for 22 h.
The aforementioned successful results prompted us to further
explore the reaction mechanism by the radical inhibition and
kinetic isotope effect (KIE) experiments. First, the radical
inhibition experiments revealed that the addition of 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO, 2.0 equiv.) and butylated
hydroxytoluene (BHT, 2.0 equiv.) as
a radical quencher,
Scheme 4. Control experiments for reaction mechanism.
respectively, partially inhibits the reaction (Scheme 4, a). This
This article is protected by copyright. All rights reserved.

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
pyrido-benzodiazepine product 2j gave an unsymmetrical N-
methyl and N’-ethyl substituted pyrido-benzodiazepine 2ja
(Scheme 5). Bromo group of benzene ring further reacts with
NaN3 in the presence of CuI as a catalyst to delivered the NH2
functionalized pyrido-benzodiazepine product 2jb. The structure
of resulting product 2jb was confirmed by the X-ray
crystallography (Scheme 5).
In order to determine whether the transformation undergoes C-H
activation, we have designed a control experiment (Scheme 4, d).
It is found that when methyl is introduced into C2 of benzimidazole
ring (A), the reaction can still proceed to give the ring opening
product but no benzodiazepine ring product was formed. The
results suggest that C-H activation is not involving in the reaction
process.
As shown in Figure 1, the DFT calculations were performed for
explore the possible pathway associated with the structural
transformation from I to V. The first step is the water-assisted
proton transfer, which coupled with the C-N bond breaking for the
transformation from intermediate I to II via transition state TSI-II.
The next step is the deprotonation process of aldehyde by
Ag2CO3 to form III via TSII-III. In the third step, it is the other
deprotonation process of pyridine ring by the other Ag2CO3 via
transition state TSIII-IV. The last step is the C–C bond formation
step via transition state TSIV-V. The calculated energy barriers are
31.4, 28.5, 28.5, and 33.7 kcal/mol via transition states TSI-II, TSII-
III, TSIII-IV, and TSIV-V, indicating that the reaction can occur under
the heating condition.
Scheme 5. Functionalization of the pyrido-benzodiazepine.
Conclusion
In conclusion, a new method for one-step synthesis of the pyrido-
benzodiazepine backbones and its analogues based on a
successive ring-opening hydrolysis of benzimidazole salts and
intramolecular C−H bond activation is reported. The procedure
featured broad substrate scope, together with excellent functional
group tolerance, affording products in moderate to excellent
yields. One significant and advantageous feature of this new
strategy lies in easy operation (without removal of moisture and
oxygen), atom- and step-economy. The experiments using
radical-scavenging reagents indicated that a radical pathway may
be not involved in this reaction transformation. The kinetic isotope
effect (KIE) experiments suggested that C-H bond cleavage at C-
3 position to pyridine ring was not the rate-limiting step. The
control experiments and density functional theory calculations
(DFT) were performed to support a possible reaction process. We
believe this practical and convenient synthetic procedure will find
promising uses in constructing pharmaceutically important pyrido-
benzodiazepine.
Figure 1. The possible reaction progress confirmed by DFT
calculations (distance in angstrom).
In traditional method, two NH group of the pyrido-benzodiazepine
generally suffer from poor site selectivity or the multistep
procedures (Scheme 2, both pathway 1 and 2) when they are
functionalized. The synthetic utility of this transformation in
comparation with the common strategy was next explored.
Further transformation of the obtained N-methyl substituted the
This article is protected by copyright. All rights reserved.

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
Voelter, J. Med. Chem. 2009, 52, 6484-6488; i) P. R. Carlier, H. Zhao, S.
L. MacQuarrie-Hunter, J. C. DeGuzman, D. C. Hsu, J. Am. Chem. Soc.
2006, 128, 15215-15220.
Computational Methods
The DFT calculations were performed using the Gaussian 16
program.[24] All structures were fully optimized at the
B3LYP[25]/DGDZVP level in THF solvent using the integral
equation formalism polarizable continuum model (IEF-PCM).[26]
Then, frequency calculations at the same level of theory were
carried out to identify all of the stationary points as minima (zero
imaginary frequency) or transition state (only one frequency), and
to provide free energies.
[3]
a) J. C. Wu, T. C. Warren, J. Adams, J. Proudfoot, J. Skiles, P. Raghavan,
C. Perry, I. Potocki, P. R. Farina, P. M. Grob, Biochem. 1991, 30, 2022-
2026; b) D. E. H. Palladino, J. L. Hopkins, R. H. Ingraham, T. C. Warren,
S. R. Kapadia, G. J. Van Moffaert, P. M. Grob, J. M. Stevenson, K. A.
Cohen, J. Chromatogr. A 1994, 676, 99-112.
[4]
[5]
[6]
a) M. Asif, Mini-Rev. Med. Chem. 2014, 14, 1093-1103; b) M. Eltze, E.
Mutschler, G. Lambrecht, Eur. J. Pharmacol. 1992, 211, 283-293; c) G.
Caselli, M. P. Ferrari, G. Tonon, G. Clavenna, M. Borsa, J. Pharm. Sci.
1991, 80, 173-177.
a) F. Shi, X. Xu, L. Zheng, Q. Dang, X. Bai, J. Comb. Chem. 2008, 10,
158-161; b) J. F. F. Liegeois, J. Bruhwyler, J. Damas, T. P. Nguyen, E.
M. G. Chleide, M. G. A. Mercier, F. A. Rogister, J. E. Delarge, J. Med.
Chem. 1993, 36, 2107-2114.
Acknowledgements
a) P. Liu, T. J. Lanza, M. Chioda, C. Jones, H. R. Chobanian, Y. Guo, L.
Chang, T. M. Kelly, Y. Kan, O. Palyha, X.-M. Guan, D. J. Marsh, J. M.
Metzger, K. Ramsay, S.-P. Wang, A. M. Strack, R. Miller, J. Pang, K.
Lyons, J. Dragovic, J. G. Ning, W. A. Schafer, C. J. Welch, X. Gong, Y.-
D. Gao, V. Hornak, R. G. Ball, N. Tsou, M. L. Reitman, M. J. Wyvratt, R.
P. Nargund, L. S. Lin, ACS Med. Chem. Lett. 2011, 2, 933-937; b) H. R.
Chobanian, Y. Guo, P. Liu, T. J. Lanza, Jr., M. Chioda, L. Chang, T. M.
Kelly, Y. Kan, O. Palyha, X. M. Guan, D. J. Marsh, J. M. Metzger, K.
Raustad, S. P. Wang, A. M. Strack, J. N. Gorski, R. Miller, J. Pang, K.
Lyons, J. Dragovic, J. G. Ning, W. A. Schafer, C. J. Welch, X. Gong, Y.
D. Gao, V. Hornak, M. L. Reitman, R. P. Nargund, L. S. Lin, Bioorg. Med.
Chem. 2012, 20, 2845-2849.
We are grateful for the support from the National Natural Science
Foundation of China (Grant No. 21868033), Shihezi Excellent
Young Scholars (2019RC01), the international cooperation
program of Shihezi University (GJHZ201908). We thank Ji-Xing
Zhao for his assistance with the single crystal X-ray diffraction,
located at the Analysis and Testing Center, Shihezi University.
Conflict of interest
[7]
a) Y. Gu, Y. Shen, C. Zarate, R. Martin, J. Am. Chem. Soc. 2019, 141,
127-132; b) C. W. Coley, W. H. Green, K. F. Jensen, Acc. Chem. Res.
2018, 51, 1281-1289.
The authors declare no conflict of interest.
[8]
[9]
G. Pepe, J.-P. Reboul, Y. Oddon, Eur. J. Med. Chem. 1989, 24, 1-13.
a) J. M. Klunder, K. D. Hargrave, M. West, E. Cullen, K. Pal, M. L. Behnke,
S. R. Kapadia, D. W. McNeil, J. C. Wu, G. C. Chow, J. Adams, J. Med.
Chem. 1992, 35, 1887-1897; b) K. D. Hargrave, J. R. Proudfoot, K. G.
Grozinger, E. Cullen, S. R. Kapadia, U. R. Patel, V. U. Fuchs, S. C.
Mauldin, J. Vitous, M. L. Behnke, J. M. Klunder, K. Pal, J. W. Skiles, D.
W. McNeil, J. M. Rose, G. C. Chow, M. T. Skoog, J. C. Wu, G. Schmidt,
W. W. Engel, W. G. Eberlein, T. D. Saboe, S. J. Campbell, A. S.
Rosenthal, J. Adams, J. Med. Chem. 1991, 34, 2231-2241.
Keywords: C-H bond activation • Silver • Cascade reaction •
Seven-membered ring • Benzodiazepine
[1]
a) B. A. Bunin, M. J. Plunkett, J. A. Ellman, Proc. Natl. Acad. Sci. USA
1994, 91, 4708-4712; b) J. Spencer, R. P. Rathnam, B. Z. Chowdhry,
Future Med. Chem. 2010, 2, 1441-1449; c) P. Filippakopoulos, J. Qi. S.
Picaud, Y. Shen, W. B. Smith, O. Fedorov, E. M. Morse, T. Keates, T. T.
Hickman, I. Felletar, M. Philpott, S. Munro, M. R. McKeown, Y. Wang, A.
L. Christie, N. West, M. J. Cameron, B. Schwartz, T. D. Heightman, N. L.
Thangue, C. A. French, O. Wiest, A. L. Kung, S. Knapp, J. E. Bradner,
Nature 2010, 468, 1067–1073; d) S. A. Kalinina, D. V. Kalinin, Y.
Hovelmann, C. G. Daniliuc, C. Muck-Lichtenfeld, B. Cramer, H. U. Humpf,
J. Nat. Prod. 2018, 81, 2177-2186; e) J. H. Ryan, J. A. Smith, C. Hyland,
A. G. Meyer, C. C. Williams, A. C. Bissember, J. Just, Progress in
Heterocyclic Chemistry 2015, 27, 531-573; f) S. G. Smith, R. Sanchez,
M. M. Zhou, Chem. Biol. 2014, 21, 573-583; g) A. Kamal, K. L. Reddy, V.
Devaiah, N. Shankaraiah, D. R. Reddy, Mini-Rev. Med. Chem. 2006, 6,
53-69; h) R. Garg, S. P. Gupta, H. Gao, M. S. Babu, A. K. Debnath, C.
Hansch, Chem. Rev. 1999, 99, 3525−3601.
[10] a) W. Hu, F. Teng, H. Hu, S. Luo, Q. Zhu, J. Org. Chem. 2019, 84, 6524-
6535; b) Y.-W. Sun, L.-Z. Wang, New J. Chem. 2018, 42, 20032-20040;
c) J. Shi, D. Zuev, L. Xu, K. A. Lentz, J. E. Grace, J. H. Toyn, R. E. Olson,
J. E. Macor, L. A. Thompson, Bioorg. Med. Chem. Lett. 2016, 26, 1498-
1502; d) U. Galli, C. Travelli, S. Aprile, E. Arrigoni, S. Torretta, G. Grosa,
A. Massarotti, G. Sorba, P. L. Canonico, A. A. Genazzani, G. C. Tron, J.
Med. Chem. 2015, 58, 1345-1357; e) A. V. Gavai, C. Quesnelle, D. Norris,
W. C. Han, P. Gill, W. Shan, A. Balog, K. Chen, A. Tebben, R. Rampulla,
D. R. Wu, Y. Zhang, A. Mathur, R. White, A. Rose, H. Wang, Z. Yang, A.
Ranasinghe, C. D'Arienzo, V. Guarino, L. Xiao, C. Su, G. Everlof, V.
Arora, D. R. Shen, M. E. Cvijic, K. Menard, M. L. Wen, J. Meredith, G.
Trainor, L. J. Lombardo, R. Olson, P. S. Baran, J. T. Hunt, G. D. Vite, B.
S. Fischer, R. A. Westhouse, F. Y. Lee, ACS Med. Chem. Lett. 2015, 6,
523-527; f) J. M. Elkins, J. Wang, X. Deng, M. J. Pattison, J. S. Arthur, T.
Erazo, N. Gomez, J. M. Lizcano, N. S. Gray, S. Knapp, J. Med. Chem.
2013, 56, 4413-4421; g) M. Binaschi, A. Boldetti, M. Gianni, C. A. Maggi,
M. Gensini, M. Bigioni, M. Parlani, A. Giolitti, M. Fratelli, C. Valli, M. Terao,
E. Garattini, ACS Med. Chem. Lett. 2010, 1, 411-415; h) X. Chen, Y.
Zheng, C. Shu, W. Yuan, B. Liu, X. Zhang, J. Org. Chem. 2011, 76, 9109-
9115; i) L. D. Fader, R. Bethell, P. Bonneau, M. Bos, Y. Bousquet, M. G.
Cordingley, R. Coulombe, P. Deroy, A. M. Faucher, A. Gagnon, N.
Goudreau, C. Grand-Maitre, I. Guse, O. Hucke, S. H. Kawai, J. E.
Lacoste, S. Landry, C. T. Lemke, E. Malenfant, S. Mason, S. Morin, J.
O'Meara, B. Simoneau, S. Titolo, C. Yoakim, Bioorg. Med. Chem. Lett.
2011, 21, 398-404; j) S. C. Lee, S. B. Park, Chem. Commun. 2007, 3714-
3716; k) R. Mossetti, D. Saggiorato, G. C. Tron, J. Org. Chem. 2011, 76,
[2]
a) J. Wang, T. Erazo, F. M. Ferguson, D. L. Buckley, N. Gomez, P.
Munoz-Guardiola, N. Dieguez-Martinez, X. Deng, M. Hao, W. Massefski,
O. Fedorov, N. K. Offei-Addo, P. M. Park, L. Dai, A. DiBona, K. Becht, N.
D. Kim, M. R. McKeown, J. M. Roberts, J. Zhang, T. Sim, D. R. Alessi, J.
E. Bradner, J. M. Lizcano, S. C. Blacklow, J. Qi, X. Xu, N. S. Gray, ACS
Chem. Biol. 2018, 13, 2438-2448; b) C. Fang, J. Cao, K. Sun, J. Zhu, T.
Lu, D. Du, Chem. Eur. J. 2018, 24, 2103-2108; c) K. Nayani, R. Cinsani,
A. Hussaini Sd, P. S. Mainkar, S. Chandrasekhar, Eur. J. Org. Chem.
2017, 2017, 5671-5678; d) P. Kralova, M. Malon, M. Soural, ACS Comb.
Sci. 2017, 19, 770-774; e) Y. Wang, B. Ling, P. Liu, S. Bi,
Organometallics 2018, 37, 3035-3044; f) H. Mtiraoui, R. Gharbi, M.
Msaddek, Y. Bretonniere, C. Andraud, C. Sabot, P. Y. Renard, J. Org.
Chem. 2016, 81, 4720-4727; g) P. Kundu, A. Mondal, B. Das, C.
Chowdhury, Adv. Synth. Catal. 2015, 357, 3737-3752; h) T. H. Al-Tel, R.
A. Al-Qawasmeh, M. F. Schmidt, A. Al-Aboudi, S. N. Rao, S. S. Sabri, W.
This article is protected by copyright. All rights reserved.

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
10258-10262; l) M. Rueping, E. Merino, R. M. Koenigs, Adv. Synth. Catal.
2010, 352, 2629-2634; m) G. Broggini, I. D. Marchi, M. Martinelli, G.
Paladino, T. Pilati, A. Terraneo, Synthesis 2005, 2246-2252; n) L. Basolo,
E. M. Beccalli, E. Borsini, G. Broggini, M. Khansaa, M. Rigamonti, Eur.
J. Org. Chem. 2010, 2010, 1694-1703.
[11] a) T. Matsufuji, K. Shimada, S. Kobayashi, M. Ichikawa, A. Kawamura,
T. Fujimoto, T. Arita, T. Hara, M. Konishi, R. Abe-Ohya, M. Izumi, Y.
Sogawa, Y. Nagai, K. Yoshida, Y. Abe, T. Kimura, H. Takahashi, Bioorg.
Med. Chem. 2015, 23, 89-104; b) A. A. Failli, J. S. Shumsky, R. J. Steffan,
T. J. Caggiano, D. K. Williams, E. J. Trybulski, X. Ning, Y. Lock, T.
Tanikella, D. Hartmann, P. S. Chan, C. H. Park, Bioorg. Med. Chem. Lett.
2006, 16, 954-959.
[12] M. L. Maddess, C. Li, Organometallics 2018, 38, 81-84.
[13] J. Verghese, C. J. Kong, D. Rivalti, E. C. Yu, R. Krack, J. Alcázar, J. B.
Manley, D. T. McQuade, S. Ahmad, K. Belecki, B. F. Gupton, Green
Chem. 2017, 19, 2986-2991.
[14] M. Tryniszewski, R. Bujok, P. Cmoch, R. Ganczarczyk, I. Kulszewicz-
Bajer, Z. Wrobel, J. Org. Chem. 2019, 84, 2277-2286.
[15] a) J. D. Neukom, A. S. Aquino, J. P. Wolfe, Org. Lett. 2011, 13, 2196-
2199; b) F. Novelli, A. Sparatore, B. Tasso, F. Sparatore, Bioorg. Med.
Chem. Lett. 1999, 9, 3031-3034.
[16] X. Diao, L. Xu, W. Zhu, Y. Jiang, H. Wang, Y. Guo, D. Ma, Org. Lett.
2011, 13, 6422-6425.
[17] P. Pertejo, N. Corres, T. Torroba, M. Garcia-Valverde, Org. Lett. 2015,
17, 612-615.
[18] L. Wang, N. Liu, B. Dai, H. Hu, Eur. J. Org. Chem. 2014, 2014, 6493-
6500.
[19] a) N. Liu, Y.-F. Xie, C. Wang, S.-J. Li, D. Wei, M. Li, B. Dai, ACS Catal.
2018, 8, 9945-9957; b) F. Chen, D. Chen, L. Shi, N. Liu, B. Dai, J. CO2
Util. 2016, 16, 391-398; c) Y.-F. Xie, C. Guo, L. Shi, B.-H. Peng, N. Liu,
Org. Biomol. Chem. 2019, 17, 3497-3506.
[20] a) F. Chen, N. Liu, B. Dai, ACS Sustainable Chem. Eng. 2017, 5, 9065-
9075; b) F. Chen, M. Li, J. Wang, B. Dai, N. Liu, J. CO2 Util. 2018, 28,
181-188.
[21] S. Tao, C. Guo, N. Liu, B. Dai, Organometallics 2017, 36, 4432-4442.
[22] a) O. Hollóczki, P. Terleczky, D. Szieberth, G. Mourgas, D. Gudat, L.
Nyulászi, J. Am. Chem. Soc. 2011, 133, 780-789; b) C. Segarra, E. Mas-
Marzá, M. Benítez, J. A. Mata, E. Peris, Angew. Chem., Int. Ed. 2012,
51, 10841-10845; c) J. Shang, B. M. Rambo, X. Hao, J.-F. Xiang, H.-Y.
Gong, J. L. Sessler, Chem. Sci. 2016, 7, 4148-4157.
[23] a) K. Murakami, S. Yamada, T. Kaneda, K. Itami, Chem. Rev. 2017, 117,
9302-9332; b) Q.-Z. Zheng, N. Jiao, Chem. Soc. Rev. 2016, 45, 4590-
4627.
[24] M. J. T. Frisch, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji,
H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.;
Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A.
F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi,
F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.;
Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery
Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers,
E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S.
S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi,
R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman,
J. B.; Fox, D. J., Gaussian16, Gaussian, Inc., Wallingford, CT, 2016.
[25] A. D. Becke, J. Chem. Phys. 1993, 98, 5648-5652.
[26] a) B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 106, 5151-5158; b) V.
Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995-2001.
This article is protected by copyright. All rights reserved.

10.1002/chem.201905828
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
RESEARCH ARTICLE
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
RESEARCH ARTICLE
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.