Titania-supported iridium subnanoclusters as an efficient heterogeneous catalyst for direct synthesis of quinolines from nitroarenes and aliphatic alcohols

Article abstract of DOI:10.1002/anie.201104089

A versatile heterogeneous catalyst consisting of sub-nanosized iridium clusters deposited on titania (Ir/TiO₂-NCs) promotes the direct tandem synthesis of quinoline derivatives from readily available nitroarenes and aliphatic alcohols under mild and additive-free conditions (see scheme). The process tolerates the presence of various reactive functional groups and is highly selective.

Full text of DOI:10.1002/anie.201104089

Communications
DOI: 10.1002/anie.201104089
Heterogeneous Catalysis
Titania-Supported Iridium Subnanoclusters as an Efficient
Heterogeneous Catalyst for Direct Synthesis of Quinolines from
Nitroarenes and Aliphatic Alcohols**
Lin He, Jian-Qiang Wang, Ya Gong, Yong-Mei Liu, Yong Cao,* He-Yong He, and Kang-
Nian Fan
Dedicated to the Fritz Haber Institute, Berlin, on the occasion of its 100th anniversary
The use of metal nanoparticles (NPs) or nanoclusters (NCs)
as versatile catalysts for green and sustainable organic
synthesis has attracted tremendous interest in recent years
owing to their unique properties, such as a large surface-to-
volume ratio and tunable shapes.[1] The control of their size,
shape, dispersity, and in particular the combination of metal
NPs/NCs with a specific heterogeneous support is essential
for enhanced activity and selectivity in a desired application.[2]
Although in many classical transformations, reusable sup-
ported metal NPs/NCs have exhibited far superior perfor-
mance than those of conventional metal complex catalysts,[3]
the possibilities offered by metal NPs/NCs for sustainable
tandem catalysis that allows a rapid increase in molecular
complexity through one-pot multistep reactions have scarcely
been explored.[4] This situation is somewhat surprising since
the integrated use of the reactive sites generated from metal
NPs/NCs and a suitable support could be a powerful means
for the design of multitask catalysts,[5] thus providing promis-
ing candidates to perform sophisticated tandem reactions for
synthesis of complex molecular targets from simple and
convenient substrates in a domino fashion.[6]
several named reactions, such as Skraup,[9] Doebner–Von
Miller,[10] Conrad–Limpach,[11] Friedlꢀnder,[12] and Pfit-
zinger[13] syntheses based on the reaction of substituted
anilines with carbonyl compounds. Despite their utility,
these methods often suffer from the requirement of costly
aromatic amines and unstable carbonyl compounds, harsh
conditions, and the use of large amounts of hazardous acids or
bases.[14] More problematic is that the complicated substituted
amines must themselves be synthesized first, mostly by
multistep procedures.[15] The development of new strategies
to obtain quinolines in a fast, clean, and efficient way has been
the focus of considerable efforts.[16] In this context, the
assembly of the quinolines directly from readily available
nitroarenes and aliphatic alcohols through a one-pot tandem
reaction is highly attractive.[17] Unfortunately, this straightfor-
ward method has proven to be extremely difficult, and
effective catalyst systems were severely limited. To date, only
two homogeneous transition-metal catalytic systems[17a,b] and
one UV-irradiated photocatalytic system[17c] have been
reported. From a synthetic and economic point of view,
these systems are not practically useful because of the
inherent problems of non-reusability, the necessity of special
handling of an external light source, or harsh conditions, as
well as low yields and limited substrate scope.
Herein, we report for the first time that a new heteroge-
neous iridium-based multitask catalyst facilitates the rapid
direct construction of valuable quinolines from nitroarenes
and alcohols under mild conditions through a facile sequential
transfer reduction–condensation–dehydrogenation pathway.
The combination of sub-nanosized iridium clusters with an
oxide support possessing suitable surface acidity, for example,
TiO2, provides an optimal catalyst. Iridium was selected
because Ir NPs and complexes are well known to catalyze a
wide range of organic transformations including dehydrogen-
ation and transfer hydrogenation.[18] The present heteroge-
neous Ir-catalyzed process shows several fundamental
improvements: 1) unprecedented catalytic efficiency;
2) unique functional group tolerance; 3) avoidance of expen-
sive ligands or additives; 4) reusability of the catalyst; and
5) high-quality products without residual heavy-metal con-
tamination. To the best of our knowledge, the reaction is
considerably greener than any of the known procedures and
involves an easy workup.
Quinolines and their derivatives are an important class of
bioactive compounds that are prescribed as antimalarial,
antibacterial, antihypertensive, and antiinflammatory drugs.[7]
In addition, quinolines are valuable synthons used for the
preparation of nanostructures and polymers that combine
enhanced electronic, optoelectronic, or nonlinear optical
properties with excellent mechanical properties.[8] The most
frequent routes to prepare functionalized quinolines include
[*] L. He, Y. Gong, Dr. Y. M. Liu, Prof. Dr. Y. Cao, Prof. Dr. H. Y. He,
Prof. Dr. K. N. Fan
Shanghai Key Laboratory of Molecular Catalysis and Innovative
Materials, Department of Chemistry, Fudan University
Shanghai 200433 (P. R. China)
E-mail: yongcao@fudan.edu.cn
Prof. Dr. J. Q. Wang
Shanghai Institute of Applied Physics, Chinese Academy of Sciences
Shanghai 201204 (P. R. China)
[**] This work was supported by the National Natural Science
Foundation of China (20873026 and 21073042), New Century
Excellent Talents in the University of China (NCET-09-0305), and the
Science and Technology Commission of Shanghai Municipality
(08DZ2270500).
Initially, the direct transformation of nitrobenzene with n-
propanol to give 2-ethyl-3-methylquinoline (3a) was inves-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104089.
10216
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Angew. Chem. Int. Ed. 2011, 50, 10216 –10220

Table 1: The synthesis of 2-ethyl-3-methylquinoline from nitrobenzene
compounds, including IrO2, bulk Ir powder, or parent TiO2, in
place of Ir/TiO2 NPs did not promote the reaction at all
(Table 1, entries 10–13).
and propanol under various conditions.[a]
Bearing in mind that particle size has been proven to be
especially influential for supported metal catalysts,[20] it is
conceived that Ir sub-nanosized clusters (< 1 nm)deposited
on TiO2 could be more effective for the direct tandem
synthesis of quinoline. To explore this possibility, an Ir/TiO2
sample with ultralow loading (0.05 wt%) was prepared. As
dertermined by high-resolution transmission electron micros-
copy (HRTEM) and the Ir L3-edge extended X-ray absorp-
tion fine structure (EXAFS), most of the Ir species were in
the region of sub-nanometers (ca. 0.9 nm, denoted as Ir/TiO2-
NCs, see Figure S2 and Table S3 in the Supporting Informa-
tion). To our delight, the yield of the desired product 3a was
obtained up to 86% in the presence of Ir/TiO2-NCs (Table 1,
entry 14). After the reaction, the Ir/TiO2-NCs could be easily
separated by filtration; inductively coupled plasma (ICP)
analysis confirmed that no Ir was present in the filtrate,
indicating that the observed catalysis is heterogeneous.
Furthermore, the recovered Ir/TiO2-NCs catalyst can be
reused, at least three times, while maintaining 100% con-
version and 71% yield at 1208C (Table 1, entry 15). There are
very few catalysts that are effective under such mild
conditions. The previously reported homogeneous ruthenium
and rhodium catalytic systems required very harsh conditions
(1808C, 5 mol% Ru or 10 mol% Rh).[17a,b] We found that,
under similar reaction conditions (i.e., 1808C), the Ir/TiO2-
NCs is about 100 times more active than the previous catalytic
systems (Table 1, entries 16–18).
The reaction profiles for the Ir/TiO2-NCs-catalyzed quin-
oline formation (see Figure S4 in the Supporting Information)
showed that aniline (1a) and dihydroquinoline (2a) were
formed initially.[21] Furthermore, it was confirmed in separate
experiments that the direct conversion of aniline and
aldehyde over Ir/TiO2-NCs gave 67% yield of 3a, while the
combination of aniline and 2-methyl-2-pentenal, the self-
aldol condensation product of propanal, led to 3a as a major
product (59% yield). These results indicate that the direct
synthesis of quinoline would proceed through a series of
consecutive steps in a cascade mode (see Scheme S1 in the
Supporting Information), in which the initial steps must be
the dehydrogenation of alcohols and transfer hydrogenation
of nitrobenzene, generating aminoarenes and aldehydes.
Then, acid-catalyzed Michael addition of aniline to the self-
aldol condensation product might occur, followed by ring
closure with dehydration to form dihydroquinoline, which
would be finally dehydrogenated to afford the quinoline
products.
Entry Catalyst
t
Conv.
Yield [%][f]
[h] [%][f]
1a
2a
3a 4a
5a
1
Ir/TiO2-NPs
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
71
55
32
9
21
41
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
100
100
4
1
6
7
3
1
1
–
–
–
–
–
–
–
3
2
1
1
63
7
5
1
6
1
1
1
4
2
1
tr
tr
–
–
–
–
–
–
–
2
3
13
8
2
Ir/CeO2
23
15
2
7
22
–
–
–
–
–
–
–
tr
6
tr
tr
3
Ir/ZnO
4
Ir/SiO2
1
5
Pt/TiO2
12 tr
6
7
8
9
10
11
12
13
14
15[b]
16[c]
17[d]
18[e]
Au/TiO2
Pd/TiO2
Ru/TiO2
Ag/TiO2
H2IrCl6·6H2O
IrO2
Ir powder
TiO2
Ir/TiO2-NCs
Ir/TiO2-NCs
Ir/TiO2-NCs
RuCl3
11
–
–
–
–
–
–
–
86
2
–
–
–
–
–
–
–
8
71 12
73 11
1.2 100
4
4
100
100
65
5
[{Rh(CO)2Cl}2]
n.m. n.m. 78 n.m. n.m.
[a] Reaction conditions: Nitrobenzene (5 mmol), propanol (20 mL),
catalyst (metal: 0.167 mol%) at 1208C, N2 atmosphere (5 atm); n.r. =no
reaction. tr=trace. n.m.=not measured. [b] Third run. [c] 1808C.
[d] Reference [17a]: nitrobenzene (40 mmol), propanol (20 mL), catalyst
(Ru: 5 mol%) at 1808C. [e] Reference [17b]: nitrobenzene (10 mmol),
propanol (15 mL), catalyst (Rh: 5 mol%), MoCl5 (Mo: 10 mol%) at
1808C, Ar atmosphere. [f] Conversions and yields based on nitrobenzene
consumption (GC analysis). Note that an appreciable amount of
azobenzene was detected in the presence of Au/TiO2 or Ir/CeO2.
tigated as a model reaction to identify the potential cata-
lysts.[19] Summarizing these experiments, we observed that
small Ir NPs (average size ca. 1.5 nm) supported on titanium
oxide (denoted as Ir/TiO2-NPs, Ir content: 1 wt%; see the
Supporting Information for preparation details) gave an
impressive conversion of nitrobenzene to afford 3a in 63%
yield at 1208C within 8 h (Table 1, entry 1). Other mineral
supports, such as CeO2, ZnO, and SiO2 resulted in low yields
(Table 1, entries 2–4). Under the same conditions, metal NPs
supported on TiO2, including Pt and Au NPs, gave poor yields
(Table 1, entries 5 and 6), whereas Pd, Ru, and Ag NPs were
completely inactive (Table 1, entries 7–9). In addition, the use
of the catlayst precursor H2IrCl6·6H2O as well as other Ir
To clarify the essential role of Ir/TiO2-NCs for the title
reaction, we investigated the catalytic performance for the
direct conversion of aniline and aldehyde at 1208C over
different Ir-free supports. As depicted in Table S1, TiO2
possessing mild surface acidity gave 41% yield of 2-ethyl-3-
methyl-1,2-dihydroquinoline (2a) in 8 h (Table S1, entry 1),
whereas CeO2 and ZnO with basic character and SiO2 with
acidic character resulted in low yield of the dihydroquinoline
intermediate (Table S1, entries 2–4). These results suggest
that the inherent surface nature of TiO2 is critical in mediating
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Communications
Table 2: Synthesis of quinoline derivatives from substituted nitroarenes
the condensation–cyclization steps involved in quinoline
and aliphatic alcohols.[a]
formation. Moreover, the lack of any nitrobenzene and
alcohol transformation over pure TiO2 strongly confirms that
the sub-nanosized Ir clusters were indispensable for promot-
ing the initial transfer reduction of nitrobenzene by using
alcohol as an in situ source of hydrogen. Furthermore,
examination of a series of Ir/TiO2 samples with various Ir
loadings (0.05, 1, 5 wt%) demonstrated that iridium clusters
with smaller particle size gave higher intrinsic activity for
direct quinoline synthesis from nitrobenzene and alcohol
(Table S2, entries 1–3), indicating that high dispersion of Ir is
beneficial for the key hydrogenation and dehydrogenation
steps. Taken together, these results indicate that a delicate
balance of cooperation between the sub-nanosized Ir clusters
and the acid sites of the TiO2 surface is essential to facilitate
the desired reaction in a domino fashion.
With these findings in hand, we started to extend this
direct tandem synthesis of quinoline derivates to a wider
range of alcohols and nitroarenes (Table 2). Other aliphatic
alcohols, including ethanol, butanol, pentanol, and hexanol,
gave the corresponding 2,3-disubstituted quinolines in
remarkably high yields (Table 2, entries 1, 3–5), considering
the steps involved. Nitrobenzenes with electron-donating and
electron-withdrawing groups in various positions reacted
smoothly (Table 2, entries 6–14). In the transformations of
methylnitrobenzenes, the lower reaction rate of o-methylni-
trobenzene relative to the m- and p-analogues indicates a
steric effect that may block ring closure to form the quinoline
skeletons (Table 2, entries 6–8). Chloro-substituted nitroben-
zenes converted into the corresponding chloro alkyl quino-
lines without any dehalogenation (Table 2, entries 9 and 10),
which was encountered in other catalytic procedures.[17c] To
further demonstrate the general applicability of our proce-
dure, we were interested in the functional group tolerance of
the catalytic system. Therefore, we studied especially chal-
lenging substrates that might undergo additional reductive
transformations. As depicted in Table 2, by employing nitro-
benzenes with sensitive substitutes such as ketone, olefin, and
carboxylic ester group as the reactants, the corresponding
quinolines were obtained in fairly good to excellent yields
(Table 2, entries 12–14). To the best of our knowledge, there is
no other example of this type of selectivity in quinolines
construction from nitroarenes and aliphatic alcohols.
Entry Nitroarene
Alcohol Product
R=
t
Yield
[h] [%][b]
78
28
1
2
3
4
5
H
(74)
86
8
CH3
(83)
92
8
C2H5
n-C3H7
n-C4H9
(89)
85
7
(81)
87
7
(84)
71
24
6
CH3
(66)
76
16
7[c]
8
CH3
CH3
CH3
CH3
CH3
(71)
69
10
(65)
60
10
9[c]
10[d]
11
(54)
67
10
(63)
78
18
(76)
68
26
12
CH3
CH3
CH3
CH3
(62)
69
17
13
(65)
68
28
14[d]
15[e]
(62)
More importantly, the present heterogeneous tandem
synthesis of quinolines could be scaled up. For example, the
direct conversion of nitrobenzene (50 mmol) and propanol in
the presence of Ir/TiO2-NCs (0.0167 mol%) at 1808C pro-
ceeds smoothly to afford 2-ethyl-3-methylquinoline in 70%
yield within 15 h (Table 2, entry 15). In this case, unprece-
dented catalyst productivity with turnover numbers (TON) of
up to 6000 was realized.
Given the importance of the quinoline nucleus in
medicinal chemistry and the excellent performance of Ir-
catalyzed quinoline synthesis under mild conditions, we
thought that the high quality alkyl quinoline obtained could
be utilized for the design of pharmacologically active
compounds. One such target with fundamental biological
interest is 2-alkenyl bisquinoline, a structure that exhibits
significant activity against intracellular amastigotes forms of
70
15
(68)
[a] Reaction conditions: Nitroarene (5 mmol), alcohol (20 mL), Ir/TiO2-
NCs (Ir: 0.167 mol%) at 1208C under N2 atmosphere (5 atm). Yields
were based on nitroarenes consumption (GC analysis). [b] Values in
parentheses refer to yields of isolated product. [c] Less than 3% 2,3,5-
substituted quinolines was detected. [d] 1508C. [e] Nitroarene
(50 mmol), alcohol (50 mL), Ir/TiO2-NCs (Ir: 0.0167 mol%) at 1808C
under N2 atmosphere (5 atm).
L. amazonensis and L. infantum and also against the replica-
tion of HIV-1.[22] To this end, 2-((E)-2-(quinolin-2-yl)vinyl)-
quinoline was synthesized in 51% yield (see Scheme 1) by a
convergent synthetic approach,[23] employing 2-methylquino-
line and 2-quinaldehyde as the reactants; the latter is
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Angew. Chem. Int. Ed. 2011, 50, 10216 –10220

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In conclusion, we have reported the noteworthy features
of the ligand-free Ir/TiO2-NCs catalyst for the heterogene-
ously catalyzed tandem synthesis of valuable quinoline
compounds from nitroarenes and aliphatic alcohols under
mild and additive-free conditions. The ready availability of
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Experimental Section
General procedure for the direct synthesis of quinolines from
nitroarenes and aliphatic alcohols: A mixture of nitrobenzene
(5 mmol), alcohol (20 mL), and catalyst (metal: 0.167 mol%) was
charged into an autoclave (100 mL capacity). The resulting mixture
was vigorously stirred (1000 rpm with a magnetic stir bar) at 1208C
under N2 atmosphere (5 atm) for the given reaction time. The
products were confirmed by comparison of their GC retention time
and mass, 1H, and 13C NMR spectra. The conversion and product
selectivity were determined by a GC-17 A gas chromatograph
equipped with a HP-5 column (30 m ꢁ 0.25 mm) and a flame ioniza-
tion detector (FID). For isolation, the combined organic layer was
dried over anhydrous Na2SO4, concentrated, and purified by silica gel
column chromatography.
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Received: June 15, 2011
Published online: August 26, 2011
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Keywords: alcohols · arenes · cluster compounds ·
.
heterogeneous catalysis · iridium
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