Synergistic catalysis on Fe-N: X sites and Fe nanoparticles for efficient synthesis of quinolines and quinazolinones via oxidative coupling of amines and aldehydes

Article abstract of DOI:10.1039/c9sc04060a

In this paper, we developed a reusable heterogeneous non-precious iron nanocomposite comprising metallic Fe-Fe₃C nanoparticles and Fe-N_x sites on N-doped porous carbon, which allows for highly efficient synthesis of quinolines and quinazolinones via oxidative coupling of amines and aldehydes using H₂O₂ as the oxidant in aqueous solution under mild conditions. A set of quinazolines and quinazolinones were synthesized in high yields with a broad substrate scope and good tolerance of functional groups. Characterization and control experiments disclose that a synergistic effect between the metallic Fe nanoparticles and built-in Fe-N_x sites is primarily responsible for the outstanding catalytic performance. Furthermore, the iron nanocomposite could be readily recovered for successive use without appreciable loss in catalytic activity and selectivity. This work provides an expedient and sustainable method to access pharmaceutically relevant N-heterocycles.

Full text of DOI:10.1039/c9sc04060a

Chemical
Science
View Article Online
View Journal | View Issue
EDGE ARTICLE
Synergistic catalysis on Fe–Nx sites and Fe
nanoparticles for efficient synthesis of quinolines
and quinazolinones via oxidative coupling of
amines and aldehydes†
Cite this: Chem. Sci., 2019, 10, 10283
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
c
a
Zhiming Ma,ab Tao Song, Youzhu Yuan
and Yong Yang
*
*
In this paper, we developed a reusable heterogeneous non-precious iron nanocomposite comprising
metallic Fe–Fe3C nanoparticles and Fe–Nx sites on N-doped porous carbon, which allows for highly
efficient synthesis of quinolines and quinazolinones via oxidative coupling of amines and aldehydes using
H2O2 as the oxidant in aqueous solution under mild conditions. A set of quinazolines and quinazolinones
were synthesized in high yields with a broad substrate scope and good tolerance of functional groups.
Characterization and control experiments disclose that a synergistic effect between the metallic Fe
nanoparticles and built-in Fe–Nx sites is primarily responsible for the outstanding catalytic performance.
Furthermore, the iron nanocomposite could be readily recovered for successive use without appreciable
loss in catalytic activity and selectivity. This work provides an expedient and sustainable method to
access pharmaceutically relevant N-heterocycles.
Received 14th August 2019
Accepted 20th September 2019
DOI: 10.1039/c9sc04060a
rsc.li/chemical-science
catalysts have demonstrated excellent catalytic performance for
a set of organic reactions, such as reductive amination,3a,d,e
hydrogenation of nitroarenes,1a,e,2d,e,3c,f the synthesis of nitriles,1g,2j
Introduction
The development of reusable earth-abundant and inexpensive
non-precious metal catalysts for innovative organic synthesis is
a key technology for a more sustainable production of ne
chemicals, pharmaceuticals and agrochemicals. Conventional
nanostructured non-precious metal catalysts prepared by
impregnation or immobilization are generally only applicable for
organic transformations of structurally simple molecules. To
further explore their broad application for more challenging and
complex synthetic reactions, great efforts have been devoted to
rational design and fabrication of nanostructured non-precious
metal catalysts with higher potential over the past few decades.
Consequently, a number of effective nanostructured non-
precious metal (e.g., Fe,1 Co,2 Ni,3 and Mn4) catalysts with unique
structures or compositions have been developed via pyrolysis of
either a mixture of metal complexes and/or carbon support1c–e,2-
and oxidation of alcohols2k,l,4a,c–e and N-heterocycles.1d,2m
Among them, nanostructured Fe catalysts are much more
attractive due to the earth-abundant, non-toxic, biocompatible,
and environmentally benign characteristics of Fe. Specically,
Fe–nitrogen-coordinated carbon catalysts, named Fe–N–C, have
recently emerged as a fascinating catalyst for electrocatalysis, in
which Fe–Nx sites are arguably considered as catalytically active
sites.5 Yet, the exploration of Fe–N–C for organic synthesis is
still scarce to date.1c Furthermore, recent studies disclosed the
presence of Fe–Nx sites in hybrid nanostructured Fe catalysts
which were proposed to be responsible for high catalytic reac-
tivity,1e while no clear and solid evidence was observed or
intense investigation was done to support such a hypothesis so
far. As such, elucidation of the role of Fe–Nx sites in catalysis is
urgently desirable, not only for better understanding the reac-
tions but also for the rational design and preparation of highly
active and stable nanostructured Fe–N–C catalysts.
c,2e,f,3b,e
(or Al2O3 (ref. 1f and 2b) or SiO2 (ref. 2c and 3f)), or
a mixture of metal salts and renewable biomass,14 or metal–
organic frameworks (MOFs).2g–i The resulting nanostructured
N-heterocycles are ubiquitous in nature and constitute the
backbone of numerous natural products, pharmaceutically
important molecules, and organic functional materials.6 Among
various N-heterocycles known, quinazolines and quinazoli-
nones are two classes of fused structural motifs with a wide
range of pharmacological and biological activities, such as
antibacterial, anti-inammatory, anticonvulsant, antimalarial,
antiasthmatic, anti-Alzheimer, and anticancer,7 and are found
in many drugs available on the market (Scheme 1).
aQingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of
Sciences, Qingdao 266101, P. R. China
bUniversity of Chinese Academy of Sciences, Beijing, 100049, P. R. China
cState Key Laboratory of Physical Chemistry of Solid Surface, National Engineering
Laboratory for Green Chemical Productions of Alcohols-Ethers-Esters, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
† Electronic supplementary information (ESI) available: Experimental section,
supplementary gures and tables, and 1H/13C NMR spectroscopy and HR-MS
data for all compounds. See DOI: 10.1039/c9sc04060a
This journal is © The Royal Society of Chemistry 2019
Chem. Sci., 2019, 10, 10283–10289 | 10283

View Article Online
Chemical Science
Edge Article
Given the importance of N-heterocycles, a number of details in the ESI†). The as-prepared catalyst was denoted as Fe–
synthetic methods have been developed over the past few Fe3C@NC-800. For comparison, Fe–Fe3C@NPC-700 and 900
decades.8 Despite these signicant advances, the most classical pyrolyzed at 700 and 900 C were also prepared with the same
ꢀ
and general approaches for the synthesis of quinazolines and preparation procedure. The Fe content in the catalysts was
quinazolinones still strongly rely on the condensation between determined to be 4.29–4.51 wt% by inductively coupled plasma
o-aminobenzylamines and aldehydes followed by the oxidation optical emission spectrometry (ICP-OES) (Table S1†).
of the resulting aminal intermediates in the laboratory and
We initiated our studies of the synthesis of quinazolines via
industry. However, this protocol generally requires the use of the oxidative coupling of 2-aminobenzylamine (1a) with benz-
a large excess of toxic oxidants, such as DDQ,9 MnO2,10 aldehyde (2a) as a model reaction using Fe–Fe3C@NC-800 as the
PhI(OAc)2,11 and NaClO,12 or homogeneous transition metal catalyst to optimize the reaction conditions (Table 1). A set of
complexes ligated with well-dened ligands,8d,13 which signi- parameters including the addition amount of benzaldehyde or
cantly limit its practical application, especially for pharmaceu- the oxidant, solvents and reaction temperatures were inten-
tical synthesis. Therefore, the development of efficient, stable sively screened. The reaction was rst performed using 1.2
and cost-effective heterogeneous non-precious metal catalysts equivalents of benzaldehyde (with respect to 1a) in the absence
for accessing quinazolines and quinazolinones is highly of an oxidant in H2O at 100 ꢀC. 95% conversion of 1a was
desirable.
In this work, we develop a novel nanostructured iron catalyst
observed, affording 1,2,3,4-tetrahydro-2-phenylquinazoline
derived from pyrolysis of a mixture of iron salt and readily
available and renewable N-containing biomass, bamboo shoots,
in a facile preparation method. The resultant catalysts comprise
mixed phases, including metallic Fe and Fe3C nanoparticles
(NPs) and Fe–Nx sites, which exhibited excellent catalytic
activity for the oxidative coupling of amines and aldehydes to
access N-heterocycles using H2O2 as a green and sustainable
oxidant in water under mild conditions. A set of pharmaceuti-
cally relevant quinazolines and quinazolinones were synthe-
sized in high yields with a broad substrate scope and good
tolerance of functional groups. Further studies reveal that
synergistic catalysis on Fe/Fe3C NPs and Fe–Nx sites is primarily
responsible for the high efficiency of the reactions. Moreover,
the catalyst could be easily recycled several times without
signicant loss in catalytic activity.
Table 1 Optimization of reaction conditionsa
GC
yieldb
(%)
Entry
Catalyst (Fe mol%)
Solvent
Conversionb (%)
I
3a
1c
2
Fe–Fe3C@NC-800
Fe–Fe3C@NC-800
Fe–Fe3C@NC-800
Fe–Fe3C@NC-800
Fe–Fe3C@NC-800
H2O
H2O
H2O
H2O
95
96
83
71
100
88
18
44
36
5
7
78
39
35
95
3d
4e
5
H2O–
THF
H2O–
THF
H2O–
THF
H2O–
THF
H2O–
THF
H2O–
THF
H2O–
THF
H2O–
THF
H2O–
THF
H2O–
THF
Results and discussion
6f
Fe–Fe3C@NC-800
Fe–Fe3C@NC-700
Fe–Fe3C@NC-900
Fe2O3
83
88
90
18
29
46
34
89
15
20
12
6
63
76
84
12
26
43
32
49
3
Nanostructured iron catalysts were prepared in
a facile
sequential hydrothermal-pyrolysis process according to
a similar procedure as that reported by us.14 The biochar ob-
tained from hydrothermal treatment of bamboo shoots was
homogeneously mixed with Fe(NO3)3 in aqueous solution at 60
ꢀC for 2 h. Aer evaporation of water, the solid powder was
pyrolyzed under a constant nitrogen ow at 800 ꢀC for 2 h (see
7
8
9
6
10
11
12
13
14g
Fe3O4
3
Fe(NO3)3
3
Nano Fe
2
Fe(II)Pc
40
12
—
a
Reaction conditions: 2-aminobenzylamine (1a) (0.2 mmol),
benzaldehyde (2a) (0.24 mmol), catalyst (4 mol% of Fe), H2O2 (2
equivalents with respect to 1a, 30 wt% in H2O), H2O (5 mL) or H2O–
b
THF (5 mL, 4/1, v/v), 100 ꢀC, 12 h. Determined by GC and GC-MS
using 1,3,5-trimethyl-benzene as an internal standard sample and
c
conrmed with their corresponding authentic samples. In the
d
e
f
absence of an oxidant. 80 ꢀC. 60 ꢀC. Fe-Fe3C@NC-800 (2 mol% of
g
Scheme 1 Selected examples of market available drugs with quino-
lone and quinazolinone skeletons.
Fe). In the absence of a catalyst.
10284 | Chem. Sci., 2019, 10, 10283–10289
This journal is © The Royal Society of Chemistry 2019

View Article Online
Edge Article
Chemical Science
intermediate (I) as the major product with only 7% GC yield of Fe3C@NC-800 and H2O2 as the oxidant is essential for the
the desired 2-phenylquinazoline 3a (entry 1). To our delight, successful synthesis of 2-phenylquinazoline in high yield.
78% GC yield of 3a was obtained when 2.0 equivalents of H2O2
Given such impressive ndings, we next investigated the
as the oxidant were used under otherwise identical conditions structural properties of the catalyst Fe–Fe3C@NC-800 by means
(entry 2). A further increase of the amount of H2O2 resulted in of comprehensive technical skills. The transmission electron
a gradual decrease in the yield of the desired 3a (Table S2†). 1.2 microscope image (Fig. 1A) shows that nanoparticles with an
equivalents of benzaldehyde was found to be the most appro- average size of 14 nm are homogeneously dispersed on carbon.
priate ratio for the synthesis of 3a in terms of catalytic activity High resolution TEM images (Fig. 1B and C) further reveal that
and selectivity (Table S3†). A decrease of either the loading of mixed metallic Fe and Fe3C NPs as the core were covered with
the catalyst Fe–Fe3C@NC-800 or reaction temperature led to a few layers of a graphitic carbon shell as shown in Fig. 1E. The
a lower yield of 3a (entries 3, 4, and 6). Further studies show that well-resolved lattice spacing of 0.204, 0.238, and 0.338 nm is
a mixture H2O–THF (v/v, 4/1) as the solvent could pronouncedly consistent with the Fe (110), Fe3C (210), and graphitic C (002)
improve the catalytic efficiency, and the yield of 3a could reach planes, respectively. High-angle annular dark-eld scanning
as high as 95% under otherwise identical conditions (entry 5 transmission electron microscopy (HAADF-STEM) images
and Table S4†). For comparison, the catalysts Fe–Fe3C@NC-700 (Fig. 1D) demonstrate the homogeneous distribution of Fe, N, O
and Fe–Fe3C@NC-900 were employed for the reaction, and both and C atoms over the entire sample. The X-ray diffraction (XRD)
showed a relatively lower activity (entries 7 and 8). In addition, pattern (Fig. 1F) discloses the formation of crystalline phases of
control experiments employing commercially available Fe2O3, metallic Fe and Fe3C with the appearance of characteristic
Fe3O4, Fe(NO3)3, iron phthalocyanine (Fe(II)Pc), and nano Fe diffraction peaks at 44.7ꢀ and 65ꢀ and at 37.6ꢀ, 37.7ꢀ, 39.8ꢀ,
powder as catalysts for the reaction show that all exhibited 40.6ꢀ, 42.9ꢀ, 43.7ꢀ, 44.9ꢀ, 45.9ꢀ and 49.1ꢀ, corresponding to the
inferior reactivity (entries 9–13). However, in the absence of the (110) and (200) phases of cubic metallic Fe (JCPDS no. 06-0696)
catalyst, the reaction took place sluggishly to produce inter- and the (121), (210), (002), (201), (211), (102), (220), (031), (112),
mediate I as the major product (entry 14). These observations (221) planes of Fe3C (cementite, JCPDS no. 35-0772), respec-
clearly indicate that the combination of the catalyst Fe– tively. Besides, a broad bump peak at 26.1ꢀ together with a tiny
peak at 43.1ꢀ indicates the formation of graphitic carbon upon
Fig. 1 (A) TEM and (B and C) HR-TEM images of the catalyst Fe–Fe3C@NC-800; the inset shows the size distribution of metallic Fe nanoparticles.
(D) HAADF-STEM and the corresponding EDX elemental mappings of individual Fe–Fe3C@NC-800, (E) schematic illustration of the catalyst Fe–
Fe3C@NC-800, and (F) XRD pattern of the catalyst Fe–Fe3C@NC-800.
This journal is © The Royal Society of Chemistry 2019
Chem. Sci., 2019, 10, 10283–10289 | 10285

View Article Online
Chemical Science
Edge Article
ꢀ
pyrolysis at 800 C. These observations are in good agreement
Taking all characterization results into account, we can
with HR-TEM results. The Raman spectrum (Fig. S2†) provided conclude that the as-prepared catalyst Fe–Fe3C@NC-800
solid evidence for the formation of graphitic carbon with certain comprises core–shell structured nanoparticles with metallic
graphitization and defect sites. N2 adsorption/desorption Fe and Fe3C NPs as the core and layers of graphitic carbon as
measurements (Fig. S3†) demonstrate that the catalyst Fe– the shell and coordinated Fe–Nx sites as well. To unveil the
Fe3C@NC-800 possess hierarchically micro-, meso-, and mac- catalytically active sites for the oxidative coupling reaction,
ropores with a high specic surface area and large pore volume a set of control experiments were carried out. First, the cata-
(Table S1†).
lyst Fe–Fe3C@NC-800 was leached with acid to remove the
The N 1s XPS spectrum (Fig. 2A) shows 4 deconvoluted peaks metallic Fe NPs, denoted as Fe–Nx@NC-800 (see details in the
at 398.2, 399.6, 400.4, and 401.3 eV, which are assignable to ESI†). The HRTEM images and XRD pattern of the acid-etched
pyridinic, Fe–Nx, pyrrolic, and quaternary N, respectively.5i,14c,d catalyst Fe–Nx@NC-800 (Fig. S7 and S8†) show that no nano-
The Fe 2p XPS spectrum (Fig. 2B) shows 3 peaks, and the peak at particles were found with preserved hollow-centered graphitic
706.8 eV in the Fe 2p3/2 spectrum can be attributed to zero- carbon layers. Such a nding further veries the core–shell
valence Fe (metallic iron or carbide), while the peak at 710.4 eV structure of the catalyst Fe–Fe3C@NC-800. When the acid-
can be assigned to Fe in the Fe(II)–Nx conguration.5c–e etched catalyst Fe–Nx@NC-800 was subjected to the optimized
Compared with Fe(II)Pc, 0.9 eV shi to a higher value was reaction conditions for the benchmark reaction, a remarkable
observed, implying the interaction of Fe–Nx and metallic Fe decrease in both conversion of 1a and yield of 3a was
NPs.5h,15 To further investigate the local iron structure of the observed, as shown in Fig. 3. This result indicates that
catalyst Fe–Fe3C@NC-800, X-ray absorption spectroscopy (XAS) metallic Fe NPs are necessary for the high catalytic activity,
was performed. The spectroscopy of Fe K-edge X-ray absorption especially for the oxidative dehydrogenation to form the
near edge structure (XANES) reveals that the catalyst Fe- aromatized product 3a. It is known that SCNÀ ions can poison
Fe3C@NC-800 almost overlaps with that of Fe(II)Pc, indicating Fe–Nx sites in catalysis.1c,5h Second, the benchmark reaction
the possible remaining Fe–N4 structure (Fig. 2C), which is was performed using the acid-etched catalyst Fe–Nx@NC-800
further conrmed from the Fe K-edge extended X-ray absorp- with the addition of NaSCN under otherwise identical condi-
tion ne structure (EXAFS) in Fig. 2D. From the shape and tions. In this case, a further decrease in activity was achieved,
˚
amplitude of the rst strong peak at z1.5 A, it is clear that the clearly implying that Fe–Nx sites indeed boost the reaction. In
bonding environment in the rst shell of the catalyst Fe– parallel, Fe(II)Pc is more active for coupling but with lower
Fe3C@NC-800 is notably similar to that of Fe(II)Pc, suggesting selectivity to 3a, while nano Fe powder was just in opposite
that it more likely contains FeN4 complex structures.5h,16 position (Fig. 3). In addition, the catalytic activity has a good
˚
Besides, the peaks at z2.1 A, assignable to Fe–Fe interactions, correlation with the content of Fe–Nx in the catalysts Fe–
reveals the presence of an iron-based crystalline structure in the Fe3C@NC-T as shown in Fig. S9,† that is, the higher the
catalyst Fe–Fe3C@NC-800.
content of Fe–Nx, the better the activity towards the desired
product 3a. As such, these results unambiguously corroborate
that metallic Fe and Fe3C nanoparticles and coordinated Fe–
Fig. 2 (A) The deconvoluted N 1s and (B) Fe 2p spectra of FePc and the
catalyst Fe–Fe3C@NC-800. (C) XANES spectra and (D) Fourier trans-
form (FT) of the Fe K-edge EXAFS data of the catalyst Fe–Fe3C@NC- Fig. 3 Comparison of catalytic performance over different catalysts
800, Fe foil and FePc.
for the benchmark reaction.
10286 | Chem. Sci., 2019, 10, 10283–10289
This journal is © The Royal Society of Chemistry 2019

View Article Online
Edge Article
Chemical Science
Table 2 Substrate scope for the synthesis of quinazolinesa
Nx in the catalyst Fe–Fe3C@NC-800 are synergistically
responsible for the coupling reaction to achieve excellent
catalytic activity.
Subsequently, further efforts were made to elucidate the
individual role of the catalyst Fe–Fe3C@NC-800 and the oxidant
H2O2 in this cascade coupling process. As stated above, the
combination of the catalyst Fe–Fe3C@NC-800 and oxidant H2O2
is a prerequisite for the success of the coupling to afford the
desired quinazoline 3a, which was reinforced by the control
experiments as shown in Scheme 2. In the absence of either the
catalyst or oxidant, trace amounts of 3a were achieved with the
formation of intermediate I being the major product instead
(Scheme 2, entries 2 and 4). Particularly, the coupling under-
went sluggishly in the absence of H2O2, and only 15% of 1a was
converted. This observation clearly indicates the critical role of
the catalyst Fe–Fe3C@NC-800 to efficiently boost the entire
process. Furthermore, when the intermediate I was subjected to
the standard conditions, quantitative conversion to 3a was ob-
tained (Scheme 2, entry 5). Once again, however, in the absence
of either the catalyst or oxidant, the efficiency of the oxidative
dehydrogenation is signicantly low, yielding 3a in 12% and
10% yield, respectively, under otherwise identical conditions
(Scheme 2, entries 6 and 7). As such, we can safely conclude that
the catalyst Fe–Fe3C@NC-800 participates in the condensation
and oxidation steps and signicantly facilitates the reaction,
while the oxidant H2O2 benets the dehydrogenation for
aromatization to produce N-heterocycles.
a
Reaction conditions: 2-aminobenzylamine (1a) (0.2 mmol), aldehyde
(0.24 mmol), Fe–Fe3C@NC-800 (4 mol% of Fe), H2O2 (2 equivalents
with respect to 1a, 30% in H2O), H2O–THF (5 mL, 4/1, v/v), 100 ꢀC, 12
h. Yields of isolated product are reported.
Aer identifying the optimal reaction conditions and the
catalytically active sites, we subsequently explored the gener-
ality of this protocol for the synthesis of 2-substituted quina-
zolines. As shown in Table 2, in general, various benzaldehydes
bearing electron-donating and -withdrawing groups could effi-
ciently couple with 2-aminobenzylamine (1a) to give their cor-
responding quinazolines in high yields, while benzaldehydes
substituted by electron-donating groups (2b–e) gave relatively
higher yields than those substituted with electron-withdrawing
groups (2j–m). Halogen-substituted benzaldehydes, such as ÀF,
ÀCl and ÀBr, were tolerated under the present conditions,
yielding the desired quinazolines (2f–i) in 85–95% yields.
Heterocyclic aldehydes such as 3-thiophenecarboxaldehyde (2o)
were also suitable as the coupling partner to deliver their cor-
responding quinazoline (2o) in 86% yield. In addition, aliphatic
aldehydes, such as cyclohexanecarboxaldehyde (2p), cyclo-
propanecarboxaldehyde (2q) and heptaldehyde (2r), could also
efficiently couple with 1a to give the desired quinazolines 3p, 3q
and 3r in 83%, 91% and 93% yields, respectively.
Next, we further explored the substrate scope of the oxidative
coupling of 2-aminobenzamide (4a) with various aldehydes (2)
to synthesize quinazolinones under the optimal reaction
conditions. To our delight, a broad spectrum of quinazolinones
were successfully synthesized in high isolated yields as shown
in Table 3. 2-Aminobenzamide could efficiently couple with
benzyl aldehydes bearing electron-withdrawing and electron-
donating groups as well as halogens. Likewise, heterocyclic and
aliphatic aldehydes are also tolerated under the present
conditions to deliver their corresponding quinazolinones in
high yields. In addition, substituted 2-aminobenzamides are
compatible for oxidative coupling too.
Durability/recyclability of a heterogeneous catalyst is critical
for sustainable and practical applications. To test the durability
of Fe–Fe3C@NC-800, the used catalyst was collected, washed,
and dried aer completion of an oxidative coupling experiment
for the synthesis of 2-phenylquinazoline (2a). As shown in
Fig. S10,† the catalytic activity and selectivity remained high
Scheme 2 Elucidation of the individual role of the catalyst Fe–
Fe3C@NC-800 and the oxidant H2O2.
This journal is © The Royal Society of Chemistry 2019
Chem. Sci., 2019, 10, 10283–10289 | 10287

View Article Online
Chemical Science
Edge Article
Table 3 Substrate scope for the synthesis of quinazolinonesa
Acknowledgements
The authors would like to acknowledge the nancial support
from the Key Technology R&D Program of Shandong Province
(2019GGX102075) and the 13th-Five Key Project of the Chinese
Academy of Sciences (Grant No. Y7720519KL). Y. Y also
acknowledges the support from the Royal Society (UK) for
a Newton Advanced Fellowship (NAF-R2-180695).
Notes and references
1 Selected examples of Fe-based catalysts: (a) R. Yun, S. Zhang,
W. Ma, X. Lv, S. Liu, T. Sheng and S. Wang, Inorg. Chem.,
2019, 58, 9469–9475; (b) J. Xie, K. Yin, A. Serov,
K. Artyushkova, H. N. Pham, X. Sang, R. R. Unocic,
P. Atanassov, A. K. Datye and R. J. Davis, ChemSusChem,
2017, 10, 359–362; (c) W. Liu, L. Zhang, X. Liu, X. Liu,
X. Yang, S. Miao, W. Wang, A. Wang and T. Zhang, J. Am.
Chem. Soc., 2017, 139, 10790–10798; (d) X. Cui, Y. Li,
S. Bachmann, M. Scalone, A.-E. Surkus, K. Junge, C. Topf
and M. Beller, J. Am. Chem. Soc., 2015, 137, 10652–10658;
(e) R. V. Jagadeesh, A.-E. Surkus, H. Junge, M.-M. Pohl,
¨
J. Radnik, J. Rabeah, H. Huan, V. Schunemann,
¨
A. Bruckner and M. Beller, Science, 2013, 342, 1073–1076;
(f) J. Li, J. Zhang, S. Wang, G. Xu, H. Wang and
D. G. Vlachos, ACS Catal., 2019, 9, 1564–1577; (g)
R. V. Jagadeesh, H. Junge and M. Beller, ChemSusChem,
2015, 8, 92–96.
a
Reaction conditions: 2-aminobenzamide (4) (0.2 mmol), aldehyde
(0.24 mmol), Fe–Fe3C@NC-800 (4 mol% of Fe), H2O2 (4 equivalents
with respect to 1a, 30% in H2O), H2O–THF (5 mL, 4/1, v/v), 100 ꢀC, 12
h. Yields of isolated product are reported.
2 Selected examples of Co-based catalysts: (a) G. Li, H. Yang,
H. Zhang, Z. Qi, M. Chen, W. Hu, L. Tian, R. Nie and
W. Huang, ACS Catal., 2018, 8, 8396–8405; (b) H. Huang,
M. Tan, X. Wang, M. Zhang, S. Guo, X. Zou and X. Lu, ACS
Appl. Mater. Interfaces, 2018, 10, 5413–5428; (c) F. Chen,
A.-E. Surkus, L. He, M.-M. Pohl, J. Radnik, C. Topf,
K. Junge and M. Beller, J. Am. Chem. Soc., 2015, 137,
11718–11724; (d) Z. Wei, J. Wang, S. Mao, D. Su, H. Jin,
Y. Wang, F. Xu, H. Li and Y. Wang, ACS Catal., 2015, 5,
4783–4789; (e) P. Zhou, L. Jiang, F. Wang, K. Deng, K. Lv
and Z. Zhang, Sci. Adv., 2017, 3, e1601945; (f)
F. A. Westerhaus, R. V. Jagadeesh, G. Wienhofer,
M.-M. Pohl, J. Radnik, A.-E. Surkus, J. Rabeah, K. Junge,
H. Junge, M. Nielsen, A. Bruckner and M. Beller, Nat.
Chem., 2013, 5, 537–543; (g) R. V. Jagadeesh, K. Murugesan,
A. S. Alshammari, H. Neumann, M.-M. Pohl, J. Radnik and
M. Beller, Science, 2017, 358, 326–332; (h) K. Shen, X. Chen,
J. Chen and Y. Li, ACS Catal., 2016, 6, 5887–5903; (i) X. Ma,
Y.-X. Zhou, H. Liu, Y. Li and H.-L. Jiang, Chem. Commun.,
2016, 52, 7719–7722; (j) K. Natte, R. V. Jagadeesh,
M. Sharif, H. Neumann and M. Beller, Org. Biomol. Chem.,
2016, 14, 3356–3359; (k) L. Zhang, A. Wang, W. Wang,
Y. Huang, X. Liu, S. Miao, J. Liu and T. Zhang, ACS Catal.,
2015, 5, 6563–6572; (l) W. Zhong, H. Liu, C. Bai, S. Liao
and Y. Li, ACS Catal., 2015, 5, 1850–1856; (m) A. V. Iosub
and S. S. Stahl, Org. Lett., 2015, 17, 4404–4407.
with negligible changes aer six recycles, demonstrating the
high durability of this catalyst.
Conclusion
In conclusion, we developed a reusable heterogeneous earth-
abundant iron nanostructured catalyst comprising metallic Fe
and Fe3C nanoparticles as the core covered by a few layers of N-
doped graphitic carbon and coordinated Fe–Nx sites as well in
a facile and cost-effective manner. The resultant best catalyst
Fe–Fe3C@NC-800 demonstrated excellent catalytic activity for
oxidative coupling of amines with aldehydes to access a broad
set of quinazolines and quinazolinones. The process was per-
formed in a green and sustainable manner under mild reaction
conditions with good tolerance of multifunctional groups.
Moreover, the catalyst could be readily recovered for successive
reuse without signicant loss in activity and selectivity. Syner-
gistic catalysis on Fe–Nx sites and metallic Fe–Fe3C nano-
particles is primarily responsible for the superior activity and
stability. This work not only demonstrates the potential of the
nanostructured Fe–N–C catalyst for complex synthetic reactions
but also provides a new efficient and sustainable method for the
synthesis of pharmaceutically important N-heterocycles.
3 Selected examples of Ni-based catalysts: (a) K. Murugesan,
M. Beller and R. V. Jagadeesh, Angew. Chem., Int. Ed., 2019,
58, 5064–5068; (b) P. Ryabchuk, A. Agapova,
Conflicts of interest
There are no conicts to declare.
10288 | Chem. Sci., 2019, 10, 10283–10289
This journal is © The Royal Society of Chemistry 2019

View Article Online
Edge Article
C. Kreyenschulte, H. Lund, H. Junge, K. Junge and M. Beller,
Chemical Science
Prod. Rep., 2008, 25, 166–187; (d) P. M. S. Bedi, V. Kumar
and M. P. Mahajan, Bioorg. Med. Chem. Lett., 2004, 14,
5211–5213.
Chem. Commun., 2019, 55, 4969–4972; (c) F. Yang, M. Wang,
W. Liu, B. Yang, Y. Wang, J. Luo, Y. Tang, L. Hou, Y. Li, Z. Li,
B. Zhang, W. Yang and Y. Li, Green Chem., 2019, 21, 704–711;
(d) Y. Zhang, H. Yang, Q. Chi and Z. Zhang, ChemSusChem,
2019, 12, 1246–1255; (e) G. Hahn, P. Kunnas, N. de Jonge
and R. Kempe, Nat. Catal., 2018, 2, 71–77; (f) P. Ryabchuk,
G. Agostini, M.-M. Pohl, H. Lund, A. Agapova, H. Junge,
K. Junge and M. Beller, Sci. Adv., 2018, 4, eaat0761.
4 Selected examples of Mn-based catalysts: (a) J. Fei, L. Sun,
C. Zhou, H. Ling, F. Yan, X. Zhong, Y. Lu, J. Shi, J. Huang
and Z. Liu, Nanoscale Res. Lett., 2017, 12, 23; (b) E. Skliri,
S. Papadogiorgakis, I. N. Lykakis and G. S. Armatas,
ChemPlusChem, 2017, 82, 136–143; (c) K. Dhanalaxmi,
R. Singuru, S. K. Kundu, B. M. Reddy, A. Bhaumik and
J. Mondal, RSC Adv., 2016, 6, 36728–36735; (d) J. Mondal,
P. Borah, S. Sreejith, K. T. Nguyen, X. Han, X. Ma and
Y. Zhao, ChemCatChem, 2014, 6, 3518–3529; (e) H.-Y. Sun,
Q. Hua, F.-F. Guo, Z.-Y. Wang and W.-X. Huang, Adv. Synth.
Catal., 2012, 354, 569–573.
7 (a) H. Li, L. He, H. Neumann, M. Beller and X.-F. Wu, Green
Chem., 2014, 16, 1336–1343; (b) A. T. Baviskar, C. Madaan,
R. Preet, P. Mohapatra, V. Jain, A. Agarwal, S. K. Guchhait,
C. N. Kundu, U. C. Banerjee and P. V. Bharatam, J. Med.
Chem., 2011, 54, 5013–5030; (c) G. Marzaro, A. Guiotto and
A. Chilin, Expert Opin. Ther. Pat., 2012, 22, 223–252; (d)
J. P. Michael, Nat. Prod. Rep., 2008, 25, 166–187; (e)
D. Sharma, B. Narasimhan, P. Kumar, V. Judge, R. Narang,
E. D. Clercq and J. Balzarini, Eur. J. Med. Chem., 2009, 44,
2347–2353.
8 Selected examples for the synthesis of N-heterocycles: (a)
Y. Liang, Z. Tan, H. Jiang, Z. Zhu and M. Zhang, Org. Lett.,
2019, 21, 4725–4728; (b) T. Chatterjee, D. I. Kim and
E. J. Cho, J. Org. Chem., 2018, 83, 7423–7430; (c) X. Yu,
L. Gao, L. Jia, Y. Yamamoto and M. Bao, J. Org. Chem.,
2018, 83, 10352–10358; (d) S. Parua, R. Sikari, S. Sinha,
G. Chakraborty, R. Mondal and N. D. Paul, J. Org. Chem.,
2018, 83, 11154–11166; (e) I. Khan, A. Ibrar, N. Abbas and
A. Saeed, Eur. J. Med. Chem., 2014, 76, 193–244; (f) B. Han,
X.-L. Yang, C. Wang, Y.-W. Bai, T.-C. Pan, X. Chen and
W. Yu, J. Org. Chem., 2012, 77, 1136–1142.
5 Selected examples of Fe-N-C catalysts: (a) X. Wan, X. Liu,
Y. Li, R. Yu, L. Zheng, W. Yan, H. Wang, M. Xu and J. Shui,
Nat. Catal., 2019, 2, 259–268; (b) X. Fu, N. Li, B. Ren,
G. Jiang, Y. Liu, F. M. Hassan, D. Su, J. Zhu, L. Yang,
Z. Bai, Z. P. Cano, A. Yu and Z. Chen, Adv. Energy Mater.,
2019, 9, 1803737; (c) H. Wang, F.-X. Yin, N. Liu, R.-H. Kou,
9 S. Rachakonda, P. S. Pratap and M. V. B. Rao, Synthesis, 2012,
44, 2065–2069.
X.-B. He, C.-J. Sun, B.-H. Chen, D.-J. Liu and H.-Q. Yin, Adv. 10 Z. Zhang, M. Wang, C. Zhang, Z. Zhang, J. Lu and F. Wang,
Funct. Mater., 2019, 29, 1901531; (d) Y. Mun, S. Lee, Chem. Commun., 2015, 51, 9205–9207.
K. Kim, S. Kim, S. Lee, J. W. Han and J. Lee, J. Am. Chem. 11 M. Saha, P. Mukherjee and A. R. Das, Tetrahedron Lett., 2017,
Soc., 2019, 141, 6254–6262; (e) Q. Wang, Y. Lei, Z. Chen, 58, 2044–2049.
N. Wu, Y. Wang, B. Wang and Y. Wang, J. Mater. Chem. A, 12 Y.-Y. Peng, Y. Zeng, G. Qiu, L. Cai and V. W. Pike, J.
2018, 6, 516–526; (f) G. Yang, W. Choi, X. Pu and C. Yu, Heterocycl. Chem., 2010, 47, 1240–1245.
Energy Environ. Sci., 2015, 8, 1799–1807; (g) Q. Lin, X. Bu, 13 A. E. Wendlandt and S. S. Stahl, J. Am. Chem. Soc., 2014, 136,
A. Kong, C. Mao, X. Zhao, F. Bu and P. Feng, J. Am. Chem. 506–512.
Soc., 2015, 137, 2235–2238; (h) W.-J. Jiang, L. Gu, L. Li, 14 (a) T. Song, Z. Ma and Y. Yang, ChemCatChem, 2019, 11,
Y. Zhang, X. Zhang, L.-J. Zhang, J.-Q. Wang, J.-S. Hu,
Z. Wei and L.-J. Wan, J. Am. Chem. Soc., 2016, 138, 3570–
3578; (i) J. Li, S. Ghoshal, W. Liang, M.-T. Sougrati,
F. Jaouen, B. Halevi, S. McKinney, G. McCool, C. Ma,
X. Yuan, Z.-F. Ma, S. Mukerjee and Q. Jia, Energy Environ.
1313–1319; (b) T. Song, P. Ren, Y. Duan, Z. Wang, X. Chen
and Y. Yang, Green Chem., 2018, 20, 4629–4637; (c)
Y. Duan, T. Song, X. Dong and Y. Yang, Green Chem., 2018,
20, 2821–2828; (d) X. Dong, Z. Wang, Y. Duan and Y. Yang,
Chem. Commun., 2018, 54, 8913–8916.
Sci., 2016, 9, 2418–2432; (j) L. Jiao, G. Wan, R. Zhang, 15 Y. Chen, S. Ji, Y. Wang, J. Dong, W. Chen, Z. Li, R. Shen,
H. Zhou, S.-H. Yu and H.-L. Jiang, Angew. Chem., Int. Ed.,
2018, 57, 8525–8529; (k) L. Jiao and H.-L. Jiang, Chem,
2019, 5, 786–804.
6 (a) K. Nepali, H.-Y. Lee and J.-P. Liou, J. Med. Chem., 2019, 62,
2851–2893; (b) P. D. Leeson and B. Springthorpe, Nat. Rev.
Drug Discovery, 2007, 6, 881–890; (c) J. P. Michael, Nat.
L. Zheng, Z. Zhuang, D. Wang and Y. Li, Angew. Chem., Int.
Ed., 2017, 129, 1–6.
16 (a) G. Wu, K. L. More, C. M. Johnston and P. Zelenay, Science,
2011, 332, 443–447; (b) J. Yang, D.-J. Liu, N. N. Kariuki and
L. X. Chen, Chem. Commun., 2008, 329–331.
This journal is © The Royal Society of Chemistry 2019
Chem. Sci., 2019, 10, 10283–10289 | 10289