Pd-catalyzed intramolecular aerobic oxidative C-H amination of 2-aryl-3-(arylamino)quinazolinones: Synthesis of fluorescent indazolo[3,2-b]quinazolinones

Article abstract of DOI:10.1021/ol5026553

A palladium-catalyzed intramolecular aerobic oxidative C-H amination of 2-aryl-3-(arylamino)quinazolinones has been developed, providing a variety of substituted indazolo[3,2-b]quinazolinone derivatives in moderate to excellent yields. Preliminary mechani

Full text of DOI:10.1021/ol5026553

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Intramolecular Aerobic Oxidative C−H Amination of
2‑Aryl-3-(arylamino)quinazolinones: Synthesis of Fluorescent
Indazolo[3,2‑b]quinazolinones
Weiguang Yang, Jiuxi Chen,* Xiaobo Huang, Jinchang Ding, Miaochang Liu, and Huayue Wu*
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, P. R. China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed intramolecular aerobic oxidative C−
H amination of 2-aryl-3-(arylamino)quinazolinones has been developed,
providing a variety of substituted indazolo[3,2-b]quinazolinone deriva-
tives in moderate to excellent yields. Preliminary mechanistic studies
suggested that a palladacycle dimer could be the key intermediate, which
underwent a cascade “rollover” cyclometalation and C−H amination
sequence. Furthermore, the potential utility of these products has been
demonstrated as a new class of blue fluorophores for fluorescent
materials.
Scheme 1. Strategies for the Synthesis of
Indazolo[3,2‑b]quinazolinones
he development of new C−H amination technology has
1
Tbeen a research area of intense interest. In contrast to the
traditional metal-catalyzed C−N cross-coupling reactions by
employing prefunctionalized substrates,2 the direct C−H
amination is a highly appealing synthetic strategy, as it utilizes
the abundant C−H bond in nature.3 The intramolecular C−H
amination provides a straightforward approach for the synthesis
of N-containing heterocycles.4 The general issue of C−H
activation using a directing group-assisted strategy is the tedious
installation/removal of these groups from the reaction
substrates/products,5−9 but this might not be a problem if
these directing groups are a required functionality in the
product for further manipulation.
Nitrogen-containing heterocycles have been widely used as
directing groups in metal-catalyzed C−H functionalization
reactions,10 but the use of quinazolinone in selective C−H
functionality has been less explored.11 Also, the resulting
indazolo[3,2-b]quinazolinone derivatives are important bio-
logically active molecules and potent inhibitors of phosphdies-
terase 4 (PDE4).12b To the best of our knowledge, the previous
examples of synthesis of indazolo[3,2-b]quinazolinones have
been limited to the use of arylhalides as coupling partners
(Scheme 1a-1c).12 Under this background, the development of
new C−H functionalization synthetic strategies for the
preparation of indazolo[3,2-b]quinazolinones still remains
highy desirable.
Our interest in the development of new methods for metal-
catalyzed C−H activation13a and the synthesis of quinazoli-
none-based fused poly-N-heterocycles12c,13b led us to explore
this transformation. We herein report a new synthetic
procedure for the preparation of indazolo[3,2-b]quinazolinones
by palladium-catalyzed intramolecular C−H amination of 2-
aryl-3-(arylamino)quinazolinones with molecular oxygen as the
ideal terminal oxidant14 under mild conditions (Scheme 1d).
We began our investigation by examining the conversion of
2-phenyl-3-(phenylamino)quinazolinone (1a) into 5-phenyl-
indazolo[3,2-b]quinazolinone (2a) (Table 1). After an initial
screen, we found that the use of 5 mol % Pd(OAc)2 in DMF at
120 °C under an oxygen atmosphere afforded 2a in 23% yield
(see Table 1, entry 1, and entries 1−11 of Table S1 in the
Supporting Information (SI)). The yield of 2a was increased to
35% with 4 Å molecular sieves15 as an additive. Encouraged by
this promising result, we further screened other reaction
parameters in order to obtain more satisfactory results. Among
the different bases evaluated, sodium bicarbonate was the
optimal base as the yield was increased to 89% with the
combination of palladium acetate (Table 1, entry 4). Other
bases (see Table 1, entries 1−3, and entries 12−17 of Table S1
in the SI) and Other palladium catalysts (see Table 1, entries
5−9, and entries 19−23 of Table S1 in the SI) exhibited lower
efficiencies. In the absence of the palladium catalyst, no or only
a trace amount of the desired 2a was detected (Table 1, entry
Received: September 7, 2014
Published: October 7, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
Pd catalyst
base
gas atm
yield (%)
c
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cs2CO3
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
air
23 (35)
11
2
tBuOK
3
NaOAc
73
4
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
89
5
46
6
Pd(PPh3)4
Pd(acac)2
PdCl2(PPh3)2
Na2PdCl4
17
7
58
8
38
9
59
10
11
12
13
trace
45
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
N2
N2
trace
d
0 (46)
a
Reaction conditions: 1a (0.2 mmol), Pd catalyst (5 mol %), base (1.0
b
c
equiv), and solvent (5 mL), 120 °C, 48 h. Isolated yield. With MS 4
Å (60 mg). 46% yield of 2-phenylquinazolin-4(3H)-one was obtained
d
with 1.5 equiv of Cu(OAc)2 as an oxidant.
10). Catalytic activity was also found under an air atmosphere,
though the formation of 2a was slower (Table 1, entry 11). In
contrast, this reaction did not work under a N2 atmosphere
(Table 1, entry 12). It is worth noting that 1a was dissociated
into 2-phenylquinazolin-4(3H)-one in 46% yield via N−N
bond cleavage without any cyclized product in the presence of
Cu(OAc)2 under a N2 atmosphere (Table 1, entry 13). Other
oxidants such as AgOAc, K2S2O8, benzoquinone (BQ), and
PhI(OAc)2 were also less effective (see entries 24−27 of Table
S1 in the SI).
With the optimial reaction conditions in hand, the scope of
this C−H amination was examined (Figure 1). The influence of
substitutions on the N-aryl ring moiety of the 2-aryl-3-
(arylamino)quinazolinone was first investigated. The steric
effects of substituents had an obvious impact on the efficiency
of this transformation. For example, when substrates bearing a
para-, meta-, and ortho-methyl group were examined, 2b and 2c
were obtained in 92% and 90% yield respectively, while little-to-
no target product 2d possessing an ortho-methyl group was
detected. The electronic properties of the substituents on the
N-aryl ring moiety affected the yields to some extent. In
general, the N-aryl ring moiety bearing an electron-donating
substituent (e.g., −Me) (compounds 2b−2c) generally
produced a higher yield than those analogues bearing an
electron-withdrawing substituent (e.g., −F, −Cl, and −CF3)
(compounds 2e−2g). No observation of the desired products
2h and 2i from 3-(benzylamino)-2-phenylquinazolinone (1h)
and N-(4-oxo-2-phenylquinazolin-3(4H)-yl)benzamide (1i)
could indicate that the electronic properties of the N-
substituted moiety (R1) are necessary for this process.
Figure 1. Synthesis of indazolo[3,2-b]quinazolinones. Reaction
conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), NaHCO3 (1.0
equiv), MS 4 Å (60 mg), and DMF (5 mL), O2, 120 °C, 48 h. Isolated
yields are provided in parentheses.
amino)-2-(m-tolyl)quinazolinone (1k) was subjected to this
procedure, the para position intramolecular C−H amination
product 2k was obtained in 78% yield with high regioselectivity.
It is noteworthy that no cyclization product was detected using
ortho-substituted on aromatic Ar2 3-(phenylamino)-2-(o-tolyl)-
quinazolinone (1l) as a substrate under the standard
conditions. Substrate 2-(4-cyanophenyl)-3-(phenylamino)-
quinazolinone (1m) bearing a strong electron-withdrawing
cyano group delivered the desired product 2m in moderate
yield. The ability to incorporate the whole tolerance of a range
of halogen substituents makes this method particularly
appealing. Substrates with para-halogenated aromatic Ar2
were used under standard conditions, leading to the
corresponding halogen-substituted products 2n, 2o, and 2p,
which may enable further access to more complex compounds
in various transformations. However, we found that 5-
phenylindazolo[3,2-b]quinazolinone (2a) was obtained in
62% yield involving C−Br bond cleavage/C−N bond
formation when an ortho halogenated aromatic Ar2 of substrates
such as 2-(2-bromophenyl)-3-(phenylamino)quinazolinone
(1u) was used (Scheme 2, eq 1). When a heterocycle-
substituted substrate, such as 2-(furan-2-yl)-3-(phenylamino)-
quinazolinone (1q), was used, the product 2q could not be
detected and almost 90% of 1q was recovered. Finally, several
substituents (e.g., −Me and −OMe, and −Cl) on aromatic Ar1
of substrates were also examined. The results showed that
electron-rich functionalities were beneficial for this trans-
formation and the corresponding products 2r and 2s were
obtained in 85% and 79% yield, respectively. In contrast,
electron-withdrawing substituents made the reactions less
Next, we turned our attention to the effect of the various
electron-donating and -withdrawing groups on aromatic Ar2 of
substrates (compounds 2j−2q). The results showed that
electron-donating goups had more favorable effects than
electron-withdrawing goups. Similarly, the intramolecular C−
H amination takes place at the less hindered C−H bond
position (compounds 2j−2l). Interestingly, when 3-(phenyl-
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Letter
Scheme 2. Pd-Catalyzed Intramolecular Amination of 1u
Scheme 3. Intramolecular Amination of 1u or 1v
Scheme 4. Plausible Reaction Pathway
effective, which may arise from the decreased electron density
on the phenyl ring. When 7-chloro-2-phenyl-3-(phenylamino)-
quinazolinone (1t) was used as the substrate, for example, the
desired product 2t was isolated in 73% yield.
It is worth mentioning that 2-(naphthalen-1-yl)-3-(phenyl-
amino)quinazolinone (1v) was proven to be a suitable
substrate, affording excellent regioselective β-position intra-
molecular C−H amination product 2v in 72% yield instead of
α-position amination product 2v-1 (Scheme 2, eq 2).
To gain a better understanding of the catalytic mechanism,
we tried to isolate and identify the carbopalladation
intermediate. Gratifyingly, the C−H insertion palladacycle
dimer complex 3 was prepared by the reaction of 1a with a
stoichiometric amount of Pd(OAc)2 in CH2Cl2 at 60 °C. The
X-ray crystallography results show that complex 3 adopts a
head-to-tail U-shaped geometry (Figure 2). The structure of
formation afforded the indazolo[3,2-b]quinazolinones (2).
However, a detailed mechanism of the formation of the
indazolo[3,2-b]quinazolinones remain unclear at the current
stage.
Because a number of nitrogen-containing heterocycles were
fluorescent and could be developed as good fluorophores,18
herein, we investigated the photophysical properties of the
resulting indazolo[3,2-b]quinazolinone derivatives. Their UV−
vis absorption and fluorescence spectra were recorded and the
corresponding data are collected in CHCl3 (see Figure S1,
Figure S2, and Table S2 in the Supporting Information). Most
of these derivatives display four obvious absorption peaks in the
region from 241 to 377 nm and emit the blue fluorescence in
the range of 424−453 nm in CHCl3. It can be conclued that the
introduction of different electron-donating and -withdrawing
groups to the Ar1 or Ar2 of the indazolo[3,2-b]quinazolinone
skeleton has a slight influence on their photophysical
properties. These compounds show large Stokes shifts over
68 nm, which is beneficial for the detection of the emission
wavelength by avoiding the interference from the excitation
wavelength.19 Additionally, the fluorescence efficiency (ΦF) of
these compounds is in the range of 0.034−0.56, using quinine
sulfate solution (ΦF = 0.55 in 0.5 mol/L H2SO4) as the
fluorescence reference.20 Notably, among these compounds,
the compound 2m exhibited the largest absorption wavelength
(377 nm) and emssion wavelength (453 nm), and the highest
ΦF value (0.56), which should be attributed to the introduction
of a strong electron-withdrawing cyano group.21 These results
indicate that indazolo[3,2-b]quinazolinones have great poten-
tial as a new class of small-molecule fluorophores.
Figure 2. Proposed intermediate and X-ray structure of 3.
complex 3 confirmed the hypothesis that the sp2-nitrogen atom
in the quinazolinone ring instead of the sp3-nitrogen atom in
the arylamino group is involved in directing C−H activation,
which is consistent with the better coordination ability of the
sp2-nitrogen atom with palladium. This implied that the direct
C−H amination could proceed through complex 3. Further-
more, we found complex 3 can be smoothly converted to 2a in
the presence of NaHCO3 in DMF at 120 °C under an oxygen
atmosphere (Scheme 3).
On the basis of these above experimental results, a possible
reaction pathway for the formation of indazolo[3,2-b]-
quinazolinones was proposed (Scheme 4). The first step may
involve the C−H bond activation of 2-aryl-3-(arylamino)-
quinazolinones (1), leading to the key C−H insertion
intermediate 3. Then, a “rollover” cyclometalation16,17 of
intermediate 3 and subsequent intramolecular C−N bond
In summary, we have developed an original approach for the
synthesis of indazolo[3,2-b]quinazolinone derivatives by Pd-
catalyzed C−H bond activation/intramolecular amination of 2-
aryl-3-(arylamino)quinazolinones. In addition, the catalytic
reaction with O2 as the terminal oxidant generates water as
the only byproduct and provides a “greener” approach to
indazolo[3,2-b]quinazolinones. More detailed mechanistic
studies and the investigation of new applications of
quinazolinone as a directing group are now being undertaken
in our laboratory.
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Synlett 2012, 23, 1364.
Experimental procedures, analytical data, NMR spectra, and X-
ray data of complex 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jiuxichen@wzu.edu.cn (J.C.).
*E-mail: huayuewu@wzu.edu.cn (H.W.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21102105 and 21172175) for financial support.
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