“On-Water” Palladium-Catalyzed Tandem Cyclization Reaction for the Synthesis of Biologically Relevant 4-Arylquinazolines

Article abstract of DOI:10.1002/chem.201903464

The quinazoline scaffold is prevalent in pharmaceutically relevant molecules that show diverse biological activities. Herein, we report an efficient “on-water” palladium-catalyzed tandem cyclization reaction from commercially available arylboronic acids and benzonitriles that enable the rapid access to 4-arylquinazoline scaffolds in good to excellent yields (45 examples, up to 98 % yield). This protocol has shown good functional group tolerance and broad substrate scope. The reaction was also performed on a gram scale and successfully applied to the synthesis of the highly potent and selective PI3Kδ inhibitor N11, showing the practicability and synthetic utility of the protocol. In this reaction, the quinazoline scaffold is efficiently constructed with the simultaneous formation of one C?C bond and one C?N bond. Collectively, the protocol could serve as an alternative strategy to synthesize biologically important quinazoline scaffolds.

Full text of DOI:10.1002/chem.201903464

A Journal of
Accepted Article
Title: Palladium-catalyzed ‘on-water’ tandem cyclization reactions for
the synthesis of biologically important 4-arylquinazolines
Authors: Shuo Yuan, Bin Yu, and Hong-Min Liu
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To be cited as: Chem. Eur. J. 10.1002/chem.201903464
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Palladium-catalyzed ‘on-water’ tandem cyclization reactions for
the synthesis of biologically important 4-arylquinazolines
Shuo Yuan,[a] Bin Yu*[a] and Hong-Min Liu*[a]
Abstract: The privileged quinazoline scaffold is prevalent in
pharmaceutically relevant molecules that show diverse biological
activities. Herein we report an efficient palladium-catalyzed ‘on-
water’ tandem cyclization reactions from commercially available
arylboronic acids and benzonitriles that enable rapid access to the 4-
arylquinazoline scaffolds in good to excellent yields (45 examples,
up to 98% yield). This protocol has shown good functional group
tolerance and broad substrate scope. The reaction was also
performed on a gram scale and successfully applied to the synthesis
of highly potent and selective PI3Kδ inhibitor N11, showing the
practicability and synthetic utility of the protocol. In this reaction, the
quinazoline scaffold is efficiently constructed with one C-C bond and
one C-N bond formed simultaneously. Collectively, the protocol
could serve as an alternative strategy to synthesize biologically
important quinazoline scaffolds.
processes for the treatment of neuroinflammation) (Figure 1).[11]
Because of unique structural features and interesting biological
properties of 4-phenylqunazolines, the design of new protocols
for the construction of this privileged scaffold has attracted
considerable interest.[12]
Water is widely used as green solvent in organic synthesis due
to its environmentally friendly nature and unique reactivity.[1]
Especially, under ‘on water’ conditions,
a
remarkable
Figure 1. Representative bioactive 4-phenylquinazolines.
phenomenon of substantial rate acceleration is observed when
insoluble reactants are stirred in aqueous suspension.[2] In this
context, Lemal and co-workers demonstrated an efficient ‘on
water’ protocol that enabled the construction of 1,2-diazetidines
from quadricyclane and azodicarboxylates via [2σ+2σ+2π]
cycloaddition.[3] Rideout and Breslow reported the Diels-Alder
reactions between nonpolar compounds, which showed much
higher reactivity in water than those performed in organic
solvents, and the rate acceleration was mostly ascribed to the
hydrogen bonding and micellar catalysis of water.[4] Grieco et al.
reported that water could promote the Claisen rearrangement in
an efficient manner.[5] Moreover, the unique characters of water
such as poor solubility, high polarity and heat capacity as well as
extensive H-bond donating (HBD) ability make water an
attractive medium for organic reactions.[6]
Quinazolines are one of the privileged nitrogen containing
heterocycles that are prevalent in natural products and synthetic
molecules with diverse pharmacological properties, including
anti-inflammatory, anticonvulsant, antiviral, anticancer, and
antimicrobial activities.[7] In particular, the 4-phenylquinazolines
(highlighted in red in Figure 1) have been found in some
bioactive molecules such as AM-2099 (selective NaV1.7 inhibitor
for the treatment of chronic pain),[8] NTRC-808 (novel NTS2
agonist for the treatment of visceral pain and psychosis),[9] N11
(selective PI3Kδ inhibitor developed by Novartis, efficacious in
vivo for the treatment of inflammatory diseases),[10] and
translocator protein (TSPO) ligand (regulation of cellular
Although some methods for constructing the quinazoline
scaffolds have been documented, strategies that enable efficient
access to the 4-phenylquinazolines from benzonitriles are still
rare.[13] Chen and Liu groups described
procedure for the synthesis of 4-phenylquinazolines via the
2+2+2] cascade annulation of benzonitriles with
a single-step
[
diaryliodonium salts (or aryldiazonium salts) (Scheme 1a).[14]
The Chen group developed a palladium-catalyzed three-
component tandem addition/cyclization reactions of 2-
aminobenzonitriles, aldehydes and arylboronic acids
(Scheme 1b) [15]
Recently, He and co-workers demonstrated
.
the synthesis of 4-aryl quinazolines by the iron-catalyzed
C(sp3)-H oxidation and intramolecular C-N bond formation
in the presence of tert-BuOOH (Scheme 1c).[16] In 2018,
the
Chen group reported tandem procedure for the
a
preparation of diverse 4-phenylqunazolines from N-(2-
cyanoaryl)benzamides and arylboronic acids via the
sequences of carbopalladation and intramolecular
cyclization (Scheme 1d).[17] Although these methods
successfully achieved the synthesis of 4-arylquinazolines, the
development of efficient and practical methodologies for the
construction of 4-arylquinazoline scaffolds remains highly
desirable.[18] Herein, we report the Pd-catalyzed tandem
cyclization reactions for the construction of new 4-
arylquinazolines from readily available phenylboronic acids
and (E)-N'-(2-cyanophenyl)-N,N-dimethylformimidamides, in
which water is employed as the green reaction medium
(Scheme 1e). In comparison with previously reported methods,
our method could efficiently generate quinazoline scaffolds in
good to excellent yields (up to 98% yield) under mild conditions
and has been successfully applied to the synthesis of a highly
potent and selective PI3Kδ inhibitor N11.
[a]
Mr. S. Yuan, Dr. B Yu, Prof. Dr. H.-M. Liu
School of Pharmaceutical sciences, Zhengzhou University
Zhengzhou 450001, China
E-mail: yubin@zzu.edu.cn; liuhm@zzu.edu.cn.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201903464
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COMMUNICATION
acetic acid, benzoic acid and trifluoroacetic acid (TFA) were less
efficient to promote this reaction (Table 1, entries 17-20).
Interestingly, the results showed that the transformation of these
reactions depended on the acidity of additives. No desired
product was observed without the acid additive (Table 1, entry
21). Furthermore, when the catalyst loading decreased to 5
mol%, the yield of compound 3a was 83%, lower than that for 10
mol% of catalyst loading (Table 1, entry 22). Similarly, the
corresponding yield was 80% when 10 mol% of ligand was used
(Table 1, entry 23). When 1 mmol amount of 2a was used, the
yield of the product was 76% (Table 1, entry 24). Based on
above optimization, the best reaction condition was that
substituted (E)-N'-(2-cyanophenyl)-N,N-dimethylformimidamide
(1 mmol) and arylboronic acid (3 mmol) were stirred in H2O (2
o
mL) at 60 C for 6 h in the presence of Pd(acac)2 (10 mol%),
bpy (20 mol%), and TfOH (10 equiv.) (Table 1, entry 6).
Table 1. Optimization of the reaction conditions.a
Entry
1
Catalyst
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
PdCl2(dppf)
Pd2(dba)3
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acacc)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Ligand
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
PPh3
BINOL
-
Additive
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TsOH
AcOH
PhCO2H
TFA
Solvent
DMF
Dioxane
MeCN
DCM
MeOH
H2O
3a (%)b
33
2
Trace
Trace
N.D.c
60
Scheme 1. Construction of 4-arylquinazoline skeletons from benzonitriles.
3
Initially,
(E)-N'-(2-cyanophenyl)-N,N-dimethylformimidamide
4
1a (1 mmol) and phenylboronic acid 2a (3 mmol) were chosen
as model substrates to examine the reactivity in the presence of
Pd(acac)2 as catalyst (10 mol%), 2,2’-bipyridine (bpy, 20 mol%)
as ligand, and trifluoromenthanesulfonic acid (TfOH) as additive
(10 equiv.) in DMF (2 mL) at 60 ℃. Interestingly, the desired 4-
phenylquinazoline 3a was obtained in 33% yield (Table 1, entry
1). Encouraged by this result, we further optimized the reaction
conditions of the model reaction, and the results are
summarized in Table 1. We firstly screened several commonly
used solvents (Table 1, entries 2-6). To our delight, compound
3a was generated in 91% yield when the reaction was carried
out in water (Table 1, entry 6). Only a trace amount of 3a was
obtained when the reaction was performed in dioxane and
acetonitrile (Table 1, entries 2 and 3). No product was formed in
dichloromethane (Table 1, entry 4). While in methanol, 3a was
generated in 60% yield (Table 1, entry 5). Next, different
palladium catalysts were used to explore their catalytic capability
(Table 1, entries 7-11), the results revealed that Pd(acac)2 was
the best one for catalyzing this cascade reaction, only a trace
amount of by-product was formed. Compound 3a was afforded
in only 43% yield when Pd(OAc)2 was utilized. Other catalysts
such as Pd(PPh3)2Cl2, Pd(PPh3)4, PdCl2(dppf), and Pd2(dba)3
failed to deliver the desired compounds. Moreover, replacement
of 2,2’-bipyridine (bpy) with other ligands, including
triphenylphosphine (PPh3) and BINOL, resulted in relatively
lower yields (Table 1, entries 12 and 13). The yield was
extremely low in the absence of ligand (Table 1, entry 14).
Unfortunately, decreasing or increasing the reaction temperature
reduced the yields (Table 1, entries 15 and 16), it was probably
due to that the low temperature reduced the reaction efficiency,
and high temperature caused the formation of by-products.
Compared to TfOH, other acids including p-toluenesulfonic acid,
5
6
91
7
H2O
43
8
H2O
N.D.
N.D.
N.D.
Trace
48
9
H2O
10
11
12
13
14
15d
16e
17
18
19
20
21
22f
23g
24h
H2O
H2O
H2O
H2O
Trace
Trace
38
H2O
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
H2O
H2O
33
H2O
70
H2O
7%
H2O
4%
H2O
79%
N.D.
83
-
H2O
TfOH
TfOH
TfOH
H2O
H2O
80
H2O
76
a
Reaction conditions: 1a (1 mmol), 2a (3 mmol), catalyst (10 mol%), ligand
b
(20 mol%), additive (10 equiv.), solvent (2 mL), 6 h, 60 ℃. NMR yields
determined by 1H NMR using the triphenylmethane as an internal standard.
c
d
e
f
N.D. means Not Detected. At room temperature. At 100 ℃. 5 mol%
g
h
amount of catalyst was used. 10 mol% amount of ligand was used.
1
mmol amount of 2a was used.
With this optimal condition in hand, we next explored the
scope of this reaction. As shown in Table 2, the corresponding
products 3a-v were obtained in good to excellent yields (81-
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10.1002/chem.201903464
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98%) regardless of the electronic nature and position of
substitutions attached to the phenyl ring of boronic acids. For the
halogen substituted arylboronic acids, the corresponding
products 3g-m were also generated in good yields (83-92%),
although the halogen attached atom may undergo further Pd-
catalyzed cross-coupling reactions. For the substrates bearing
the electron-rich methoxy group, the products 3o-p were
obtained in relatively lower yields (81% and 83%, respectively).
Similarly, the NO2 substituted boronic acid also gave compound
3q in 82% yield. Interestingly, for substrates bearing the acetyl
and hydroxy groups at the 3-position of the phenyl ring, the
corresponding products 3r and 3s were also formed in 87 and
86%, respectively under the optimized condition. Compounds 3t-
v were afforded in excellent yields (up to 96% yield) when the
bulky 1-naphthaleneboronicacid, β-naphthylboronic acid, and 4-
biphenylboronic acid were used.
arylboronic acids. As shown in Table 3, except for compounds
4h and 4i, other 4-arylquinazolines were generated in good to
excellent yields (74-98%) under the optimized conditions. For
substrates bearing the electron-donating groups, the
corresponding products 4j-l were obtained in excellent yields
(92-98%). For the NO2 substituted substrate, the product 4m
was formed in 71% yield. The results suggest that the electronic
nature of substitutions attached to the phenyl ring of (E)-N'-(2-
cyanophenyl)-N,N-dimethylformimidamides is crucial for the
reactivity. For substrates bearing halogen atoms or alkyl groups,
the corresponding products were obtained in good yields as well.
To our surprise, for substrates bearing halogen atoms adjacent
to the CN group, no desired products were formed. We
speculate that the steric hindrance of the halogen atom
hampered the formation of the desired products. To prove the
synthetic practicality of this method, the reaction was performed
on a 1.0 gram scale under slightly modified conditions, the
corresponding compound 4e was formed in 67% yield.
Table 2. Scope of arylboronic acids a
Table 3. Scope of (E)-N'-(2-cyanophenyl)-N,N-dimethylformimidamides a
a Reaction conditions: 1a (1 mmol), 2 (3 mmol), Pd(acac)2 (10 mol%), bpy (20
mol%), TfOH (10 equiv.), H2O (2 mL), 60 ℃, 6 h.
a Reaction conditions: 1a (1 mmol), 2 (3 mmol), Pd(acac)2 (10 mol%), bpy (20
mol%), TfOH (10 equiv.), H2O (2 mL), 60 ℃, 6 h. b Conditions: 1a (1.01g, 4
mmol), 2 (3.6 g, 20 mmol), Pd(acac)2 (10 mol%), bpy (20 mol%), TfOH (15
equiv.), H2O (8 mL), 80℃, 12 h.
Given the good reactivity of compound 1a with diverse
arylboronic acids, we further investigated the scope of other (E)-
N'-(2-cyanophenyl)-N,N-dimethylformimidamides
and
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To further illustrate the synthetic utility, this method was then
applied to the synthesis of N11 (Figure 1), which is a highly
potent and selective PI3Kδ inhibitor developed by Novartis for
the treatment of inflammatory diseases.[10] Under the slightly
modified condition, the key intermediate 4e was efficiently
synthesized in 67% yield on a gram scale. In contrast,
Compound 4e had been previously synthesized in an overall
yield of 48%, which involved four consecutive steps and harsh
reaction conditions.[10, 19] With the key intermediate 4e in hand,
N11 was efficiently obtained through the reported routine
methods as shown in Scheme 2.[10, 20] Conceivably, our protocol
could also be applicable to the synthesis of other 4-
phenylquinazoline derivatives, such as AM-2099, NTRC-808
and TSPO ligand (Figure 1).
access to the quinazoline scaffolds in good to excellent yields
(45 examples, up to 98% yield). This protocol has shown well
functional group tolerance and broad substrate scope. The
reaction was also performed on a gram scale, affording
compound 4e in 67% yield. The protocol was successfully
applied to the synthesis of highly potent and selective PI3Kδ
inhibitor N11, showing the practicability and synthetic utility of
the protocol. In this reaction, the quinazoline scaffold was
efficiently constructed with one C-C bond and one C-N bond
formed simultaneously. Compared with previously reported
methods, the method presented in this work has several
advantages such as mild reaction conditions, short reaction time,
ease of product isolation, particularly the use of water as the
solvent. To conclude, the protocol developed could serve as an
efficient alternative strategy to synthesize biologically active 4-
phenylquinazoline derivatives.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 81773562 and 81703326), China
Postdoctoral Science Foundation (Nos. 2018M630840 and
2019T120641), and Scientific Program of Henan Province (No.
182102310123).
Scheme 2. Synthesis of selective PI3Kδ inhibitor N11.
Based on the aforementioned results, a plausible mechanistic
pathway is depicted in Scheme 3. Intermediate A was formed
from 1a by the coordination of the arylpalladium species
generated in situ from the palladium catalyst and arylboronic
acid. Next, through carbopalladation of the cyano group and
protonation of the imine, a palladium ketamine complex B was
provided. The complex B then underwent protonation and
intramolecular nucleophilic addition to generate species C,
which was then subjected to aromatization, affording the desired
quinazoline 3. Clearly, through the palladium-catalyzed on-water
tandem cyclization reactions, the quinazoline scaffold was
efficiently constructed with one C-C bond and one C-N bond
formed simultaneously.
Keywords: Palladium catalysis • On-water synthesis • Cascade
reactions • Quinazolines
[1] a) P. Norcott, C. Spielman, C. S. P. McErlean, Green Chem. 2012, 14,
605; b) H.-X. Song, Q.-Y. Han, C.-L. Zhao, C.-P. Zhang, Green Chem.
2018, 20, 1662; c) G. V. Oshovsky, D. N. Reinhoudt, W. Verboom,
Angew. Chem., Int. Ed. 2007, 46, 2366; d) H. Weingartner, E. U.
Franck, Angew. Chem., Int. Ed. 2005, 44, 2672; e) L. L. K. Taylor, I. A.
Riddell, M. M. J. Smulders, Angew. Chem., Int. Ed. 2019, 58, 1280; f) V.
C. Nibali, M. Havenith, J. Am. Chem. Soc. 2014, 136, 12800.
[2] a) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B.
Sharpless, Angew. Chem., Int. Ed. 2005, 44, 3275; b) B. Basu, K.
Biswas, S. Kundu, S. Ghosh, Green Chem. 2010, 12, 1734; c) S. Zhu,
C.-Q. Chen, M.-Y Xiao, L.-P Yu, L. Wang, J. Xiao, Green Chem. 2017,
19, 5653; d) S. Pelliccia, V. Abbate, F. Meneghetti, N. Frascione, R. C.
Hider, E. Novellino, G. C. Tron, M. Giustiniano, Green Chem. 2018, 20,
3912; e) A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725; f) S. Y.
Lee, C.-H. Cheon, J. Org. Chem. 2018, 83, 13036.
[3] N. Rieber, J. Alberts, J. A. Lipsky, D. M. Lemal, J. Am. Chem. Soc. 1969,
91, 5668.
[4] D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816.
[5] P. A. Grieco, E. B. Brandes, S. McCann, J. D. Clark, J. Org. Chem. 1989,
54, 5849.
[6] a) S. Gao, H. Liu, Z.-J. Wu, H.-Q. Yao, A. Lin, Green Chem. 2017, 19,
1861; b) Z. P. Demko, K. B. Sharpless, J. Org. Chem. 2001, 66, 7945;
c) H. Hayashi, S. Ogo, T. Abura, S. Fukuzumi, J. Am. Chem. Soc. 2003,
125, 14266; d) H. Kanemitsu, K. Uehara, S. Fukuzumi, S. Ogo, J. Am.
Chem. Soc. 2008, 130, 17141; e) P. A. Grieco, K. Yoshida, P. Garner, J.
Org. Chem. 1983, 48, 3137; f) V. V. Fokin, K. B. Sharpless, Angew.
Chem., Int. Ed. 2001, 40, 3455.
[7] a) X. Cai, H. X. Zhai, J. Wang, J. Forrester, H. Qu, L. Yin, C. J. Lai, R. Bao,
C. Qian, J. Med. Chem. 2010, 53, 2000; b) C. Carmi, E. Galvani, F.
Vacondio, S. Rivara, A. Lodola, S. Russo, S. Aiello, F. Bordi, G.
Costantino, A. Cavazzoni, R. R. Alfieri, A. Ardizzoni, P. G. Petronini, M.
Mor, J. Med. Chem. 2012, 55, 2251; c) K. M. Amin, M. M. Kamel, M. M.
Scheme 3. Purposed reaction mechanism for the formation of 4-
arylquinazolines.
In summary, we have developed an efficient palladium-
catalyzed ‘on-water’ tandem cyclization reactions from readily
available arylboronic acids and benzonitriles that enable rapid
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Anwar, M. Khedr, Y. M. Syam, Eur. J. Med. Chem. 2010, 45, 2117; d) V.
G. Ugale, S. B. Bari, Eur. J. Med. Chem. 2014, 80, 447; e) A. Machara,
V. Lux, M. Kozisek, K. Grantz Saskova, O. Stepanek, M. Kotora, K.
Parkan, M. Pavova, B. Glass, P. Sehr, J. Lewis, B. Muller, H. G.
Krausslich, J. Konvalinka, J. Med. Chem. 2016, 59, 545; f) Q. Zeng, J.
Wang, Z. Cheng, K. Chen, P. Johnstrom, K. Varnas, D. Y. Li, Z. F.
Yang, X. Zhang, J. Med. Chem. 2015, 58, 8200; g) Y. Zhang, M. D.
Tortorella, J. Liao, X. Qin, T. Chen, J. Luo, J. Guan, J. J. Talley, Z. Tu,
ACS Med. Chem. Lett. 2015, 6, 1086; h) E. Jafari, M. R. Khajouei, F.
Hassanzadeh, G. H. Hakimelahi, G. A. Khodarahmi, Res. Pharm. Sc.
2016, 11, 1.
36192; f) C. Wan, J. Zhang, S. Wang, J. Fan, Z. Wang, Org. Lett. 2010,
12, 2338.
[13] a) U. P. Saikia, G. Borah, P. Pahari, Eur. J. Org. Chem. 2018, 83, 1211;
b) Y. Yan, Y. Xu, B. Niu, H. Xie, Y. Liu, J. Org. Chem. 2015, 80, 5581;
c) R. Prakash, B. R. Bora, R. C. Boruah, S. Gogoi, Org. Lett. 2018, 20,
2297.
[14] a) X. Su, C. Chen, Y. Wang, J. Chen, Z. Lou, M. Li, Chem. Commun.
2013, 49, 6752; b) M. Ramanathan, S. T. Liu, J. Org. Chem. 2017, 82,
8290.
[15] K. Hu, Q. Zhen, J. Gong, T. Cheng, L. Qi, Y. Shao, J. Chen, Org. Lett.
2018, 20, 3083.
[8] I. E. Marx, T. A. Dineen, J. Able, C. Bode, H. Bregman, M. Chu-Moyer, E. F.
DiMauro, B. Du, R. S. Foti, R. T. Fremeau, Jr., H. Gao, H. Gunaydin, B.
E. Hall, L. Huang, T. Kornecook, C. R. Kreiman, D. S. La, J. Ligutti, M.
J. Lin, D. Liu, J. S. McDermott, B. D. Moyer, E. A. Peterson, J. T.
Roberts, P. Rose, J. Wang, B. D. Youngblood, V. Yu, M. M. Weiss,
ACS Med. Chem. Lett. 2016, 7, 1062.
[16] C. Y. Chen, F. He, G. Tang, H. Yuan, N. Li, J. Wang, R. Faessler, J. Org.
Chem. 2018, 83, 2395.
[17] J. Zhu, Y. Shao, K. Hu, L. Qi, T. Cheng, J. Chen, Org. Biomol. Chem.
2018, 16, 8596.
[18] a) S. M. Baghbanian, M. Farhang, RSC Adv. 2014, 4, 11624; b) S. K.
Panjaa, S. Saha, RSC Adv. 2013, 3, 14495; c) Y. Yan, Z. Wang, Chem.
Commun. 2011, 47, 9513; d) T. Chatterjee, D. I. Kim, E. J. Cho, J. Org.
Chem. 2018, 83, 7423.
[9] J. B. Thomas, A. M. Giddings, S. Olepu, R. W. Wiethe, D. L. Harris, S.
Narayanan, K. R. Warner, P. Sarret, J. M. Longpre, S. P. Runyon, B. P.
Gilmour, Bioorg. Med. Chem. Lett. 2015, 25, 292.
[19] R. R. Yadav, S. K. Guru, P. Joshi, G. Mahajan, M. J. Mintoo, V. Kumar, S.
S. Bharate, D. M. Mondhe, R. A. Vishwakarma, S. Bhushan, S. B.
Bharate, Eur. J. Med. Chem. 2016, 122, 731.
[10] K. Hoegenauer, N. Soldermann, F. Stauffer, P. Furet, N. Graveleau, A. B.
Smith, C. Hebach, G. J. Hollingworth, I. Lewis, S. Gutmann, G. Rummel,
M. Knapp, R. M. Wolf, J. Blanz, R. Feifel, C. Burkhart, F. Zecri, ACS
Med. Chem. Lett. 2016, 7, 762.
[20] a) F. Burkhar, M. Hoffmann, H. Kessler, Angew. Chem. Int. Ed.,1997, 36,
1191; b) K. F. McDaniel, L. Wang, T. Soltwedel, S. D. Fidanze, L. A.
Hasvold, D. C. Liu, R. A. Mantei, J. K. Pratt, G. S. Sheppard, M. H. Bui,
E. J. Faivre, X. L. Huang, L. M. Li, X. Y. Lin, R. Q. Wang, S. E. Warder,
D. wilcox, D. H. Albert, T. J. Magoc, G. Rajaraman, C. H. Park, C. W.
Hutchins, J. W. J. Shen, R. P. Edalji, C. H. C. Sun, R. Martin, W. Q.
Gao, S. Wong, G. W. Fang, S. W. Elmore, Y. Shen, W. M. Kati, J. Med.
Chem., 2017, 60, 8369.
[11] S. Castellano, S. Taliani, M. Viviano, C. Milite, E. Da Pozzo, B. Costa, E.
Barresi, A. Bruno, S. Cosconati, L. Marinelli, G. Greco, E. Novellino, G.
Sbardella, F. Da Settimo, C. Martini, J. Med. Chem. 2014, 57, 2413.
[12] a) S. Yuan, B. Yu, H.-M. Liu, Adv. Synth. Catal. 2019, 361, 59; b) Y. Yan,
Y. Zhang, C. Feng, Z. Zha, Z. Wang, Angew. Chem., Int. Ed. 2012, 51,
8077; c) Z.-H. Zhang, X.-N. Zhang, L.-P. Mo, Y.-X. Li, F.-P. Ma, Green
Chem. 2012, 14, 1502; d) J. Chen, D. Chang, F. Xiao, G.-J. Deng,
Green Chem. 2018, 20, 5459; e) Y.-Z. Yan, M.-M. Shi, B. Niu, X.-P.
Meng, C.-R. Zhu, G.-Y. Liu, T. Chena, Y. Liu, RSC Adv. 2016, 6,
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10.1002/chem.201903464
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Shuo Yuan,a Bin Yu,*,a Hong-Min Liu*,a
Page No. – Page No.
An efficient palladium-catalyzed ‘on-
water’ tandem cyclization reactions
from readily available arylboronic
acids and benzonitriles has been
developed to offer rapid access to the
quinazoline scaffolds in good to
excellent yields (up to 98% yield). This
protocol is also performed on a gram
scale and successfully applied to the
Palladium-catalyzed ‘ on-water’
tandem cyclization reactions for the
synthesis of biologically important 4-
arylquinazolines
synthesis of
a highly potent and
selective PI3Kδ inhibitor N11.
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