Palladium-Catalyzed Three-Component Tandem Process: One-Pot Assembly of Quinazolines

Article abstract of DOI:10.1021/acs.orglett.8b01070

The first example of the palladium-catalyzed, three-component tandem reaction of 2-aminobenzonitriles, aldehydes, and arylboronic acids has been developed, providing a new approach for one-pot assembly of diverse quinazolines in moderate to good yields. A noteworthy feature of this method is the tolerance of bromo and iodo groups, which affords versatility for further synthetic manipulations. Preliminary mechanistic experiments indicate that this tandem process involves two possible mechanistic pathways for the formation of quinazolines via catalytic carbopalladation of the cyano group.

Full text of DOI:10.1021/acs.orglett.8b01070

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Three-Component Tandem Process: One-Pot
Assembly of Quinazolines
Kun Hu, Qianqian Zhen, Julin Gong, Tianxing Cheng, Linjun Qi, Yinlin Shao, and Jiuxi Chen*
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, P. R. China
S
* Supporting Information
ABSTRACT: The first example of the palladium-catalyzed, three-
component tandem reaction of 2-aminobenzonitriles, aldehydes, and
arylboronic acids has been developed, providing a new approach for one-
pot assembly of diverse quinazolines in moderate to good yields. A
noteworthy feature of this method is the tolerance of bromo and iodo
groups, which affords versatility for further synthetic manipulations.
Preliminary mechanistic experiments indicate that this tandem process
involves two possible mechanistic pathways for the formation of quinazolines via catalytic carbopalladation of the cyano group.
uinazoline and derivatives represent an important class
Scheme 1. Design of New Approach to Quinazolines
Q of fused nitrogen-containing heterocycles because they
are prevalent structural motifs in many natural products,
pharmaceuticals, ligands, and C−H bond activation partners.1
Therefore, the design of novel protocols to construct
quinazoline skeletons more efficiently has been an active area
of research in organic chemistry during the past several
decades.2,3 However, less attention has been paid to the
formation of quinazolines from nitriles.4
The nitrile is one of the most versatile scaffolds in both
synthetic and medicinal chemistry.5 It is well-known, however,
that nitriles have been usually used as solvents or ligands in
organometallic reactions, presumably due to the inherently
inert nature of the CN bond.6 In a pioneering report in 1999,
Larock established carbocycle synthesis via carbopalladation of
nitriles.7 The past decade has witnessed noticeable progress in
the development of transition-metal-catalyzed addition of an
organoboron reagent to nitriles.8,9 One of the principal
challenges in the field of transition-metal-catalyzed trans-
formation of nitriles that limits the application of functional
ketones or N-heterocycle synthesis is largely rooted in both
selectivity and reactivity. To achieve the high-value trans-
formation of nitriles, we have developed the palladium-
catalyzed direct addition of arylboronic acids to free amino-
substituted nitriles such as 2-aminobenzonitriles and 2-
aminophenylacetonitriles, providing a new protocol for the
synthesis of 2-aminobenzophenones and 2-arylindoles, respec-
tively (Scheme 1a).10 However, the development of an efficient
catalytic system that can incorporate the nitrogen atom of a
cyano group into N-heterocycle products, rather than under-
going hydrolysis of ketamine intermediates, still remains a
challenge. Very recently, we have successfully developed a
tandem synthesis of isoquinolines and isoquinolones via
carbopalladation of nitriles.11
(phenyl)methyl)aniline in a 3:1 ratio.12 However, treatment
of 2-(benzylideneamino)benzonitrile with PhLi delivered the
adducts 2-(benzhydrylamino)benzonitrile or N-benzhydryl-2-
(imino(phenyl)methyl)aniline.12
Compared to Grignard reagents and organolithium reagents,
organoboron reagents13 hold great promise due to their low
toxicity, ease of handling, and good functional group tolerance,
etc. The development of new transformations in which the inert
CN bond reacts as a functional group holds great promise
for expediting N-heterocycle syntheses. On the basis of the two
distinct modes of reactivity of 2-aminobenzonitriles with
As shown in Scheme 1b, the reaction of 2-
(benzylideneamino)benzonitrile with PhMgBr was conducted
in THF to produce cyclization product 2,4-diphenyl-1,2-
dihydroquinazoline and adduct N-benzhydryl-2-(imino-
Received: April 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nucleophiles (Ar1B(OH)2) and electrophiles (Ar2CHO), we
envisioned two possible reaction pathways that could involve
carbopalladation of the cyano group to deliver the desired
quinazolines (Scheme 1c). As part of our efforts on the
development of novel transformations of nitriles9−11 and
quinazoline synthesis,14 herein we report a Pd-catalyzed
tandem reaction of simple and commercially available starting
materials (2-aminobenzonitriles, aldehydes, and arylboronic
acids), providing a new and complementary method for the
synthesis of quinazolines. To our knowledge, this is the first
example of a three-component tandem quinazoline synthesis
through carbopalladation of the cyano group in one pot.
Our study commenced by examining the reaction of 2-
aminobenzonitrile (1a), phenylboronic acid (2a), and 4-
nitrobenzaldehyde (3a) for the screening of reaction conditions
(Table 1). No target product was detected with HCl as an
additive under a variety of conditions. However, when the
additive was changed to an organic acid such as CH3CO2H, a
trace amount of the desired product 2-(4-nitrophenyl)-4-
phenylquinazoline (4a) was detected by GC−MS along with
small amounts of two condensation byproducts, (E)-2-((4-
nitrobenzylidene)amino)benzonitrile and 2-aminobenzophe-
none (entry 1). The use of CF3SO3H (TfOH) as an additive
greatly increased the yield of 4a to 60% (entry 7). Other
additives, including PhCO2H, CF3CO2H, p-CH3C6H4SO3H
(TsOH), p-NO2C6H4SO3H (PNSA), and D-camphorsulfonic
acid (CSA), were less efficient (entries 2−6). Among the
Pd(II) catalysts used, Pd(acac)2 exhibited the highest catalytic
reactivity, providing 71% yield (entries 7−12). In contrast, this
transformation did not work when Pd(0) catalysts such as
Pd(PPh3)4 were used (entry 13). The choice of ligand was also
vital to the success of the catalytic reaction. Among the various
bidentate ligands tested (L2−L8) (entries 14−20), 5,5′-
dimethyl-2,2′-bipyridine (L3) achieved the best result (86%
yield, entry 15). In contrast, little to no product 4a was
observed when sterically hindered ligands, such as 6,6′-
dimethyl-2,2′-bipyridine (L4) and 2,2′-biquinoline (L5)
(entries 16 and 17), were used. Finally, we studied the solvent
effect and found that DMF was superior to THF, EtOH,
toluene, and N,N-dimethylacetamide (DMA) (entries 15 and
21−24). The reaction failed to give 4a if either palladium
catalyst or ligand was absent (entries 25 and 26).
a
Table 1. Optimization of Reaction Conditions
With the optimized conditions in hand, we proceeded to
examine the substrate scope (Scheme 2). When benzaldehydes
bearing a variety of electron-withdrawing groups, such as nitro
(4b,c), trifluoromethyl (4d), fluoro (4e), chloro (4f), and
bromo (4g), were used, the reactions proceeded smoothly, and
moderate to good yields were obtained. The reaction of
benzaldehydes bearing electron-donating groups such as methyl
(4h,i) and methoxy (4j) afforded the corresponding products
in acceptable yields. Notably, treatment of 2-naphthaldehyde
with 1a and 1b also proceeded smoothly and gave the desired
product 4k in 81% yield. It was noteworthy that steric
hindrance did not have an obvious effect on the reaction; for
example, the reactivities of p-, m-, and o-tolylboronic acid were
evaluated, and the corresponding products 4m, 4n, and 4o were
obtained in 74%, 72%, and 67% yields, respectively. A variety of
functional groups, including electron-donating groups such as
methyl (4m−o), tert-butyl (4p), methoxy (4q), and [1,3]-
dioxolo (4r) and electron-withdrawing groups such as fluoro
(4s), chloro (4t), and bromo (4u), were well tolerated.
Biphenyl-4-ylboronic acid was amenable to the reaction
conditions, affording the desired product 4v in 85% yield.
Electron-donating groups such as methyl (4w−x) and electron-
withdrawing groups such as fluoro (4y) and chloro (4z−4aa)
were tolerated in the aromatic nitrile, achieving the desired
products with moderate to good yields. Electronic effects of
substituents affected the reactivity to some extent. Both
strongly electron-withdrawing (e.g., −CF3) and electron-
donating (e.g., −OMe) groups were compatible with this
reaction, affording the corresponding products 4ab and 4ac in
73% and 86% yields, respectively. An excellent yield of 4ad was
obtained when the disubstituted substrate 2-amino-4,5-
dimethoxybenzonitrile was used.
b
entry
Pd catalyst
Pd(OAc)2
ligand
additive
solvent
yield (%)
1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L3
L3
L3
L3
L3
CH3CO2H
PhCO2H
CF3CO2H
TsOH·H2O
PNSA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
trace
11
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
3
23
4
51
5
36
6
CSA
48
7
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
60
8
trace
trace
trace
65
9
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
Pd(CF3CO2)2
Pd(acac)2
Pd(PPh3)4
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
71
0
79
86
trace
trace
45
38
30
31
EtOH
toluene
DMA
DMF
DMF
26
The development of new methods for the introduction of
halogen (e.g., bromo and iodo) substituents into target
products is attractive and promising because of their potential
for further synthetic elaborations. Next, we turned our attention
to the reaction of 2-aminobenzonitriles bearing bromo or iodo
groups such as 2-amino-5-bromobenzonitrile (1b), 2-amino-3-
bromobenzonitrile (1c), and 2-amino-5-iodobenzonitrile (1d)
to afford a diverse range of bromo- or iodo-substituted
39
62
0
Pd(acac)2
0
a
Conditions: 1a (0.3 mmol), 2a (0.75 mmol), 3a (0.6 mmol), Pd
catalyst (5 mol %), ligand (10 mol %), additive (4 equiv), KF (0.6
b
mmol), solvent (3 mL), 80 °C, 48 h, air. Isolated yield.
B
DOI: 10.1021/acs.orglett.8b01070
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Organic Letters
Letter
a
Scheme 2. Synthesis of Quinazoline Derivatives
Scheme 3. Synthesis of Bromo- or Iodo-Substituted
Quinazolines
a
a
Conditions: 1 (0.3 mmol), 2 (0.75 mmol), 3 (0.6 mmol), Pd(acac)2
(5 mol %), L3 (10 mol %), TfOH (4 equiv), KF (2 equiv), DMF (3
mL), 80 °C, 48 h, air. Isolated yield.
quinazolines (Scheme 3). In this series, the steric effects of
substituents affected the yields of the reaction to some extent.
For example, the reaction with p-, m-, and o-tolylboronic acid
efficiently afforded 5b, 5c, and 5d in 76%, 75%, and 72% yields,
respectively. However, the reaction with p-, m-, and o-
fluorophenylboronic acid was examined, and 71% of 5e and
63% of 5f were obtained, while the yield of 5g was decreased to
42%. Both electron-deficient halogens (e.g., −Cl, −Br, −I) and
electron-rich (e.g., −OMe) substituents were tolerated (5h−k),
although slightly lower yields were observed. It is worth noting
that the desired product 6-bromo-4-(naphthalen-1-yl)-2-
phenylquinazoline (5l) was isolated in 74% yield when 1-
naphthylboronic acid was used. The structure of 5l was
characterized by X-ray crystallography. The products 5m, 5n,
and 5o were obtained in 76%, 73%, and 72% yields,
respectively.
a
Conditions: 1 (0.3 mmol), 2 (0.75 mmol), 3 (0.6 mmol), Pd(acac)2
(5 mol %), L3 (10 mol %), TfOH (4 equiv), KF (2 equiv), DMF (3
mL), 80 °C, 48 h, air. Isolated yield.
arylboronic acids affected the yields of the reaction to some
extent. In general, arylboronic acids bearing an electron-
donating substituent (e.g., −Me) (5q) produced a slightly
higher yield of product than that of an analogue bearing an
electron-withdrawing substituent (e.g., −F) (5r). However, an
arylboronic acid with a strongly electron-donating group (e.g.,
−OMe) decreased the yield of 5s to 58%. Finally, the reaction
of 2-amino-5-iodobenzonitrile (1d) was further investigated.
The desired product 5t was isolated in 68% yield. Arylboronic
acids with electron-deficient halogens (e.g., −F, −Cl, −Br, − I)
and electron-rich (e.g., −OMe) substituents were compatible
with this reaction, allowing the introduction of a wide range of
functional groups into iodo-substituted quinazolines (5u−z).
The results showed that an electron-withdrawing substituent
Treatment of 2-amino-3-bromobenzonitrile (1c) with
phenylboronic acid and benzaldehyde also proceeded smoothly
and gave the desired product 5p in 82% yield. The electronic
properties of the substituents on the phenyl ring of the
C
DOI: 10.1021/acs.orglett.8b01070
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Letter
(e.g., −Br) was beneficial for this transformation, and the
corresponding product 5aa was obtained in 76% isolated yield.
In contrast, the electron-rich substituents (e.g., −Me) made the
reactions less effective, which may arise from the increased
electron density on the phenyl ring. When 4-methylbenzalde-
hyde was used as the substrate, for example, the desired product
5ab was isolated in 67% yield.
condensation reaction of 2-aminobenzonitriles and aldehydes,
followed by the coordination of the arylpalladium species from
transmetalation of the palladium catalyst with arylboronic acid
to generate intermediate B. Next, carbopalladation of the cyano
group would result in the formation of a palladium ketimine
intermediate C. In path b, the first step may involve
transmetalation between the palladium catalyst and arylboronic
acid to give the arylpalladium species, which was followed by
the coordination of the cyano group, leading to the
intermediate E. Next, the intramolecular carbopalladation of
the cyano group generates imine palladium complex F, which
would be followed by the condensation in the presence of
aldehydes to give intermediate C. The intermediate C
undergoes an intramolecular cyclization to palladium complex
D. Finally, β-hydride elimination of the intermediate D would
afford the desired quinazolines and regenerate the palladium
catalyst.
To gain insight into the reaction mechanism, further
experiments were performed, as shown in Scheme 4. (E)-2-
Scheme 4. Control Experiments
In summary, we have developed an efficient strategy for the
one-pot synthesis of quinazolines by a Pd-catalyzed three-
component tandem reaction of commercially available 2-
aminobenzonitriles, aldehydes, and arylboronic acids. This
system shows remarkable chemoselectivity and broad substrate
scope. Further studies on the scope, mechanism, and synthetic
application of this chemistry are underway in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
((4-Nitrobenzylidene)amino)benzonitrile (6a) was obtained in
42% yield when phenyboronic acid was absent (Scheme 4a).
Treatment of 1a with 2a in the absence of aldehyde afforded
(2-aminophenyl)(phenyl)methanone (7a) in 11% yield
(Scheme 4b). The desired product 4a was obtained in 70%
yield when the reaction of 6a with 2a was performed (Scheme
4c). The reaction of 2-(imino(phenyl)methyl)aniline (8a) with
3a also proceeded to give the desired product 4a in 62% yield,
accompanied by a trace amount of 7a from the hydrolysis of 8a
(Scheme 4d). These results implicate 6a or 8a as possible
intermediates for this transformation.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01070.
Experimental procedures, characterization data, NMR
spectra, and X-ray data for product 5l (PDF)
Accession Codes
CCDC 1818103 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
On the basis of the above experimental results and relevant
reports in the literature, two possible mechanistic pathways for
the formation of quinazolines are proposed in Scheme 5. In
path a, the imine intermediate A is formed from the
Scheme 5. Two Possible Mechanistic Pathways for the Formation of Quinazolines
D
DOI: 10.1021/acs.orglett.8b01070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Lindh, J.; Sjoberg, P. J. R.; Larhed, M. Angew. Chem., Int. Ed.
2010, 49, 7733. (b) Miao, T.; Wang, G. Chem. Commun. 2011, 47,
̈
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiuxichen@wzu.edu.cn.
ORCID
9501. (c) Skillinghaug, B.; Skold, C.; Rydfjord, J.; Svensson, F.;
̈
Behrends, M.; Savmarker, J.; Sjoberg, P. J. R.; Larhed, M. J. Org. Chem.
̈
2014, 79, 12018. (d) Yousuf, M.; Das, T.; Adhikari, S. New J. Chem.
2015, 39, 8763. (e) Hsieh, J. C.; Chen, Y. C.; Cheng, A.; Tseng, H. C.
Org. Lett. 2012, 14, 1282. (f) Xia, G.; Han, X.; Lu, X. Adv. Synth. Catal.
2012, 354, 2701. (g) Liu, J.; Zhou, X.; Rao, H.; Xiao, F.; Li, C.; Deng,
G. Chem. - Eur. J. 2011, 17, 7996. (h) Skillinghaug, B.; Rydfjord, J.;
Jiuxi Chen: 0000-0001-6666-9813
Notes
Savmarker, J.; Larhed, M. Org. Process Res. Dev. 2016, 20, 2005.
̈
The authors declare no competing financial interest.
(i) Malapit, C. A.; Reeves, J. T.; Busacca, C. A.; Howell, A. R.;
Senanayake, C. H. Angew. Chem., Int. Ed. 2016, 55, 326. (j) Malapit, C.
A.; Caldwell, D. R.; Luvaga, I. K.; Reeves, J. T.; Volchkov, I.; Gonnella,
N. C.; Han, Z. S.; Busacca, C. A.; Howell, A. R.; Senanayake, C. H.
Angew. Chem., Int. Ed. 2017, 56, 6999.
(9) We have also demonstrated an efficient synthesis of alkyl aryl
ketones, diketones, and 2-arylbenzofurans via carbopalladation of
nitriles; see: (a) Wang, X.; Liu, M.; Xu, L.; Wang, Q.; Chen, J.; Ding,
J.; Wu, H. J. Org. Chem. 2013, 78, 5273. (b) Chen, J.; Li, J.; Su, W. Org.
Biomol. Chem. 2014, 12, 4078.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21572162), the Natural Science Foundation of Zhejiang
Province (Nos. LY16B020012 and LQ18B020001), the Science
and Technology Project of Zhejiang Province (No.
2016C31022), and the Xinmiao Talent Planning Foundation
of Zhejiang Province (No. 2017R426050) for financial support.
(10) (a) Chen, J.; Ye, L.; Su, W. Org. Biomol. Chem. 2014, 12, 8204.
(b) Yu, S.; Hu, K.; Gong, J.; Qi, L.; Zhu, J.; Zhang, Y.; Cheng, T.;
Chen, J. Org. Biomol. Chem. 2017, 15, 4300. (c) Yu, S.; Qi, L.; Hu, K.;
Gong, J.; Cheng, T.; Wang, Q.; Chen, J.; Wu, H. J. Org. Chem. 2017,
82, 3631.
(11) (a) Hu, K.; Qi, L.; Yu, S.; Cheng, T.; Wang, X.; Li, Z.; Xia, Y.;
Chen, J.; Wu, H. Green Chem. 2017, 19, 1740. (b) Qi, L.; Hu, K.; Yu,
S.; Zhu, J.; Cheng, T.; Wang, X.; Chen, J.; Wu, H. Org. Lett. 2017, 19,
218.
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