Heterogeneous Palladium-Catalyzed Hydrogen-Transfer Cyclization of Nitroacetophenones with Benzylamines: Access to C?N Bonds

Article abstract of DOI:10.1002/cctc.201601060

The first Pd/C-catalyzed oxidative C(sp³)?H bond amination of o-nitroacetophenones with benzylamines or amino acids proceeding through C?N bond cleavage followed by C?N bond formation by a hydrogen-transfer strategy was developed. These transformations proceeded smoothly in water to afford the desired quinazolines in moderate to good yields. This protocol has a broad substrate scope and good tolerance of air, offers excellent recyclability of the catalyst, and does not need any additional oxidant, ligand, or base; the combination of all of these factors give a new and practical avenue for multiple C?N bond formation. Moreover, a hot filtration experiment indicated that heterogeneous palladium nanoparticles during the reaction are the active species.

Full text of DOI:10.1002/cctc.201601060

Accepted Article
Title: Heterogeneous
Palladium-Catalyzed
Hydrogen-Transfer
Cyclization of Nitroacetophenones with Benzyl Amines: Access to
C-N Bonds
Authors: Lin Tang, Pengfei Wang, Yang Fan, Xingkun Yang, Changfeng
Wan, and Zhenggen Zha
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To be cited as: ChemCatChem 10.1002/cctc.201601060
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10.1002/cctc.201601060
ChemCatChem
COMMUNICATION
Heterogeneous Palladium-Catalyzed Hydrogen-Transfer
Cyclization of Nitroacetophenones with Benzyl Amines: Access
to C-N Bonds
Lin Tang,*[a] Pengfei Wang,[a] Yang Fan,[a] Xingkun Yang,[a] Changfeng Wan,*[b] and Zhenggen Zha[c]
Abstract: The first Pd/C-catalyzed oxidative C(sp3)-H bond
amination of o-nitroacetophenones with benzyl amines or amino
acids by C-N bond cleavage, followed by C-N bond formation via a
hydrogen-transfer strategy, has been developed. These
transformations proceed smoothly in water, affording the desired
quinazolines in moderate to good yields. This protocol represents
broad substrate scope, excellent recyclability of the catalyst and
good tolerance to air, and does not need additional oxidant, ligand
and base, which enables a new and practical avenue for multiple C-
N bond formation. Moreover, the hot filtration experiment indicates
that heterogeneous palladium nanoparticles during the reaction are
active species.
benzaldehydes (or alcohols),[10] Cu-catalyzed coupling of o-
halobenzoic acids, o-halobenzyl halides or o-halobenzyl
aldehydes with amidines[11] and other alternative approaches.[12]
Recently, interesting reactions of benzylamines and o-carbonyl
anilines were successfully exploited to synthesize 2-
arylquinazolines through amination of C(sp3)-H bond under
oxidative conditions (Scheme 1A).[13] As an ongoing effort to
synthesize C-N bonds and heterocycles,[6,14] we herein report
novel and efficient access to 2,4-disubstituted quinazolines
starting from o-nitroacetophenones and benzyl amines or amino
acids under catalysis of commercially available Pd/C (palladium
nanoparticles supported on activated carbon) (Scheme 1B).
Previous work (A):
2
Transition metal-catalyzed direct C-H bond activation has been
deemed as a powerful and efficient protocol for C-N bond
formation.[1] Accordingly, recent efforts made towards amination
of C-H bond with various amino sources via the C-H bond
activation strategy have been widely developed.[2,3,4] Since nitro
compounds are inexpensive and easily available chemical
materials and their reduction is a fundamental and significant
transformation in synthesizing various nitrogen-containing
medical and synthetic intermediates, transition metal-catalyzed
directly oxidative coupling of C-H bond with nitroarenes for
constructing C-N bond via a hydrogen-transfer strategy is highly
desirable.[5] Additionally, external oxidants are not involved in
this strategy. Recently, we[6] and others[7] have successfully
developed the hydrogen-transfer strategy for C-N bond
construction by use of nitroarenes and alcohols (or amines) as
the substrates. However, thus far, the application of this strategy
in directly oxidative amination of C(sp3)-H bond with nitro group
through C-N bond cleavage-formation sequence under
heterogeneous catalytic system has not been reported.
O
R
N
catalyst
2
R
N
1
1
Ar
NH
2
+ R
R
oxidant, solvent
NH
Ar
2
This work (B):
2
R
O
Ar
Ar
NH
2
2
Pd/C
N
R
1
1
COOH
R
+ R
water
N
Ar
NO
2
NH
2
recyclable catalyst; no external oxidant; water as the solvent
Scheme 1. Preparation of 2-arylquinazolines via oxidative C(sp3)-H bond
amination.
The initial experiment was carried out with the model reaction
of benzylamine (1a) with o-nitroacetophenone (2a) catalyzed by
Pd/C in toluene (Table 1). Since hydrogen-transfer reactions are
usually performed under alkaline conditions, we employed
different bases as the additives. Pleasingly, the corresponding
product of 3a was achieved in 74% when NaOAc was employed
(entry 1). However, the reaction was completely suppressed
when t-BuOK, NaOH or KOH was added (entries 2-4).
Interestingly, the reaction proceeded well when K2CO3, Na2CO3
or NaHCO3 with weaker alkalinity was used (entries 6-8). The
obtained results showed that the alkalinity of the additives had a
greatly negative impact on aforementioned reaction. As
expected, higher yield of 79% was obtained at the absence of
additive (entry 9). Further investigations show that reaction
temperature of 140 °C and 2 mol% of Pd/C were optimal (entries
10-14). When the reaction took place in water or under air
atmosphere, 3a was still achieved in good yield of 85% or 78%
respectively, which indicated the reaction possessed fine
tolerance of water and air (entries 15-16). Further studies
indicated that 3.0 equiv. of 1a was optimal (entries 17-18).[15]
Since water is the most easily available and nontoxic solvent in
organic synthesis,[16] we chose Entry 15 as the optimized
conditions.
Quinazolines and their derivatives are regarded as an
important class of nitrogen-containing heterocycles because of
their extensive appearance in natural products and active
molecules.[8] Generally, these compounds were prepared via
Bischler cyclization,[9] condensation of o-carbonyl anilines with
[a]
[b]
[c]
Dr. L. Tang, P. Wang, Prof. Dr. Y. Fan, Prof. Dr. X. Yang
College of Chemistry and Chemical Engineering
Xinyang Normal University
Xinyang 464000 (P. R. China)
E-mail: lintang@xynu.edu.cn
Dr. C. Wan
College of Chemistry and Chemical Engineering
Jiangxi Normal University
Nanchang 330022 (P. R. China)
E-mail: wanfeng@jxnu.edu.cn
Prof. Dr. Z. Zha
Department of Chemistry
University of Science and Technology of China
Hefei 230026 (P. R. China)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201601060
ChemCatChem
COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
had little influence on the above reaction. When we conducted
the reaction under an air atmosphere, 3b, 3d, 3n, 3t and 3u
were still obtained with good yields, which verified that fine
tolerance of air was represented in this reaction.
O
N
conditions
Ph
NH
+
2
N
Ph
NO
2
1a
2a
3a
2
O
R
Entry
Pd/C [mol %]
Additive
Temp. [°C ]
Yield [%][b]
2
o
R
N
Pd/C, 140
C
3
1
3
R
+
R
NH
2
R
1
5
5
5
5
5
5
5
5
5
5
5
5
1
2
2
2
2
2
NaOAc
130
130
130
130
130
130
130
130
130
110
140
160
140
140
140
140
140
140
74
1
NO
water
N
R
2
1
2
3
2
t-BuOK
n.d.
n.d.
n.d.
trace
65
3
NaOH
N
N
N
OMe
OMe
N
N
N
4
KOH
[a]
3a, 85%
3c, 73%
3b, 78% (70%)
5
Cs2CO3
N
N
N
6
K2CO3
O
O
N
N
N
7
Na2CO3
67
3e, 81%
[a]
3f, 64%
F
3d, 82% (71%)
8
NaHCO3
70
N
N
N
N
N
9
--
--
--
--
--
--
--
--
--
--
79
F
N
[b]
10
11
12
13
14
15[c]
16[d]
17[e]
18[f]
62
3g, 72%
3i, 46%
3h, 54%
Cl
CF
3
86
N
N
87
N
N
N
N
N
N
80
3l, 37%
[c]
3j, 21%
3k, n.d.
3m, 74%
86
F
Cl
85
78
N
N
N
N
N
75
N
N
N
[a]
3n, 74% (65%)
3o, 67%
3p, 67%
3q, 58%
84
Br
[a] Reactions conditions: 1a (0.75 mmol), 2a (0.25 mmol), toluene (1.0 ml),
additive (1.0 equiv.), 24 h, N2 atmosphere. [b] Isolated yield. [c] Water as the
solvent. [d] Air atmosphere. [e] 1a (0.50 mmol). [f] 1a (1.0 mmol).
N
N
N
N
N
N
[a]
3t, 86% (81%)
3s, n.d.
3r, 51%
The scope of various benzyl amines with nitroarenes was
extended after confirming the optimized conditions (Scheme 2).
To our delight, benzylic amines bearing electron-donating
groups could proceed smoothly, affording the corresponding
products in good yields (3b-3e). Nevertheless, electron-
withdrawing groups on the benzene ring led to slightly lower
yields (3f, 3g, 3h). Besides, only an acceptable yield of 3i
bearing strong electron-withdrawing group was obtained even
though the reaction temperature was increased to 160 °C.
Substrates of aliphatic amines within two carbon atoms were
effective (3j, 3k). Moreover, the desirable products could also be
readily achieved when R2 was replaced by cyclopentyl or
substituted aryls (3m-3r). Nevertheless, low yield of 3l was
obtained, which could be attributed to the decarboxylation of 2-
nitrobenzoic acid derived from 2-nitrobenzaldehyde. Additionally,
3s could not be obtained, perhaps due to the steric hindrance.
Good yields of 3t-3v were also achieved when R3 was methyl,
fluoro, or chloro, which indicated that the electronic effect of R3
F
N
N
N
N
N
N
Cl
O
O
[a]
3v, 77%
3u, 81% (71%)
3w, 72%
Scheme 2. Reaction conditions: 1 (0.75 mmol), 2 (0.25 mmol), Pd/C (2 mol%),
water (1.0 ml), 140 °C, 24 h, N2 atmosphere; isolated yield. [a] Air atmosphere.
[b] 160 °C . [c] 70 wt% ethylamine (1.5 mmol).
The result of 3l obtained in Scheme
2 indicated the
occurrence of decarboxylation. Encouraged by this result, we
attempted to employ amino acids as the substrates to
synthesize quinazolines via decarboxylative oxidative amination.
Pleasingly, these transformations could also proceed smoothly
when water was employed as the solvent (Scheme 3).
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COMMUNICATION
Reactions of different amino acids with o-nitroacetophenones,
regardless of electron-donating groups or electron-withdrawing
groups, yielded the corresponding products in moderate to good
yields (3a, 3c, 3f, 3h, 3n and 3t). It is a pity that the reaction was
inactive when R4 was an alkyl.
R2
O
COOH
NH2
R2
NO2
Pd/C, 140 o
C
N
R3
R4
R3
+
water
N
R4
4
2
3
N
N
OMe
N
N
N
N
3a, 89%
F
3c, 61%
3f, 67%
Ph
Figure 1. Hot filtration experiment.
N
N
N
N
N
N
Ph
Ph
O
Cl
3n, 74%
3t, 88%
3h, 52%
Pd/C (2 mol%)
N
(A)
+
N
Ph
water (1 ml)
140 oC, 4 h
Scheme 3. Reaction conditions: 4 (0.75 mmol), 2 (0.25 mmol), Pd/C (2 mol%),
water (1.0 ml), 140 °C, 24 h, N2 atmosphere; isolated yield.
N
Ph
NH2
6a
0.75 mmol
2a'
3a, not detected
0.25 mmol
O
We could easily recover this heterogeneous catalyst through
straightforward physical separation. The recyclability of
heterogeneous catalysts is one of the most important
advantages. Therefore, reuse of the catalyst for the synthesis of
3a was performed (Table 2). To our delight, 3a still was obtained
in 71% yield at the fifth run, which indicates that the catalyst
possesses an excellent recyclability in this reaction.
Pd/C (2 mol%)
NH3 (aq) (1.5 eq.)
N
(B)
+
Ph
O
water (1 ml)
140 oC, 4 h
N
Ph
NH2
5c
0.75 mmol
2a'
3a, 89%
0.25 mmol
O
O
Pd/C (2 mol%)
N
+
(C)
+
NH2
Ph
water (1 ml)
140 oC, 4 h
Table 2. Recycling of the catalyst for the synthesis of 3a.[a]
N
Ph
NO2
NO2
1a
0.75 mmol
2a
3a, 20%
2a, 73%
O
0.25 mmol
N
Pd/C, 140 o
C
Ph
NH
+
2
N
Ph
Scheme 4. Control experiments.
NO
2
water
1a
2a
3a
Run
Yield [%][b]
1
2
3
4
5
To gain insight into the possible information on the quinazoline
forming pathway, several control experiments were conducted
as shown in Scheme 4. Firstly, 3a could not be observed when
the reaction of 6a with 2a’ proceeded for 4 h under standard
conditions (A).[18] While the reaction of 5c with 2a’ was
performed in the presence of nitrogen source, 89% of 3a could
be achieved (B). The results obtained in (A) and (B) revealed
that the reaction proceeded via routes A instead of B.[19] When
1a reacted with 2a for 4 h, only 20% of 3a was obtained and
73% of 2a was recovered, which indicated that route C could
hardly take place and this hydrogen-transfer process was the
rate-determining step (C).
85
81
78
74
71
[a] Reaction conditions: 1a (0.75 mmol), 2a (0.25 mmol), Pd/C (2 mol%), water
(1.0 ml), 140 °C , 24 h, N2 atmosphere. [b] Isolated yield.
Pd/C might produce homogeneous active species of Pd
during the reaction. To verify the active species, the hot filtration
experiment in the reaction of 1a with 2a in toluene under
standard conditions was carried out (Figure 1). Once Pd/C was
removed, the reaction could not take place even though 14
ug/ml leaching form of Pd nanoparticles was detected by ICP
(inductively coupled plasma) analysis. In addition, TEM
(transmission electron microscopy) analysis signified that the
particle size of the obtained catalyst was about 4.12 nm.[17] The
above experiments absolutely proved that heterogeneous Pd
nanoparticles were the active species.
Based on control experiments and previous reports,[7c,14c,20] we
propose a plausible reaction mechanism as shown in Scheme 5.
First of all, dehydrogenation of benzylamine (1a) can produce
imine (5b) as well as the palladium-hydride species (PdH2),
which reduces 2a into 2a’ in situ. This hydrogen-transfer process
is regarded as the rate-determining step. Then, 5b can be
converted to 5c by C-N cleavage with liberation of 5d. The
condensation of 5c or 5b with 2a’ can give 5e. The C-N bond
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COMMUNICATION
General procedures for hot filtration experiment
formation reaction of 5e with 5d undergoes condensation,
followed to generate 5g by cyclization. Afterwards, the final
product 3a can be achieved from 5g and 2a via the second
hydrogen-transfer process. 1a and 5g serve as the hydrogen
donor (reductant) and 2a serves as the hydrogen acceptor
(oxidant) in the catalytic system.
Toluene (1.0 ml) was added to the mixture of 2a (0.25 mmol), 1a (0.75
mmol), and 10% Pd/C (2 mol%) in a Schlenk tube. The tube was
vacuumized to remove the air, refilled with N2 and sealed. Then, the
mixture was heated to 140 °C for 4 h. The catalyst was recovered by
filtration. The filtrate was refilled with N2 and was kept reacting for desired
time (8, 12, 16, 20 and 24 h). After reaction, the content of Pd was
detected by ICP analysis and the yield was detected by GC analysis.
N
N
NH
Ph
N
Ph
N
Ph
N
5f
H
3a
5g
PdH
Pd
Acknowledgements
2
O
O
The authors are grateful to the National Natural Science
Foundation of China (21602190, 21402068), the Foundation of
Henan Educational Committee (17A150049), the Nanhu
Scholars Program for Young Scholars of XYNU, and the
Doctoral Research Foundation of Xinyang Normal University
(15025, 15124).
hydrogen-transfer
process (second)
NH
NO
2
2
2a'
2a
2a'
5c Ph
O
NH
5d
3
5d
5d
Ph
NH
O
Ph
NH
O
2
1a
2a
5b
O
Keywords: palladium • quinazolines • heterogeneous catalysis •
hydrogen-transfer strategy • amination
PdH
Pd
2
N
Ph
5e
NO
NH
[1]
[2]
[3]
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2
2
2a'
hydrogen-transfer
process (first)
Scheme 5. Proposed reaction mechanism.
In conclusion, an efficient and novel synthetic method for
cascade preparation of quinazolines under the catalysis of Pd/C
via a hydrogen-transfer strategy has been developed. By taking
the advantage of this heterogeneous catalytic system, two C-N
bonds are formed through intermolecular oxidative amination of
C(sp3)-H Bonds with nitro group by C-N bond cleavage-
formation sequence, and decarboxylative amination is also
accomplished when amino acids are employed as the substrates.
Prominent superiorities, such as broad substrate scope, no
involvement of external oxidant, ligand, base and organic
solvent, recyclable catalyst and fine tolerance of air, were
represented in the reaction. Further studies on reaction
mechanism and its applications are currently underway in our
laboratory.
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Experimental Section
General reaction procedures for the synthesis of 3a and recycling of
the catalyst
Water (1.0 ml) was added to the mixture of 2a (0.25 mmol), 1a (0.75
mmol), and 10% Pd/C (2 mol%) in a Schlenk tube. The tube was
vacuumized to remove the air, refilled with N2 and sealed. Then, the
mixture was heated to 140 °C for 24 h. When the reaction was finished,
the mixture was extracted with EtOAc and separated by centrifugation.
Then, the obtained solid catalyst was dried under vacuum and heated at
120 °C before it was used in the next run. The organic layer was
removed in vacuo. The obtained residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 30:1) to give the final
product.
[4]
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COMMUNICATION
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For internal use, please do not delete. Submitted_Manuscript
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10.1002/cctc.201601060
ChemCatChem
COMMUNICATION
R3
H
H
An efficient synthesis of
quinazolines catalyzed by
L. Tang,* P. Wang, Y. Fan, X. Yang,
C. Wan,* Z. Zha
Pd
Pd
N
N
R2
Pd
R1
NH2
R1
O
N
R3
R3
R2
recyclable Pd/C via a hydrogen-
transfer strategy is reported.
Based on this heterogeneous
catalytic system, two C-N bonds
are formed through intermolecular
oxidative amination of C(sp3)-H
Bonds with nitro group by C-N
bond cleavage-formation
H
+
HOOC
NO2
R3 = aryl, alkyl
recyclable catalyst
water
R2
Page No. – Page No.
NH2
R4
N
R4
R1 = aryl, alkyl
Heterogeneous Palladium-
Catalyzed Hydrogen-Transfer
Cyclization of
Nitroacetophenones with Benzyl
Amines: Access to C-N Bonds
broad substrate scope
good tolerance to air
no external oxidant, ligand and base
up to 89% yield
absolutely heterogeneous process
sequence, and decarboxylative
amination is also accomplished
when amino acids are employed
as the substrates.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.