Pd/C as an efficient heterogeneous catalyst for carbonylative four-component synthesis of 4(3H)-quinazolinones

Article abstract of DOI:10.1039/c5cy00907c

Quinazolinones are of interest in the fields of pharmaceuticals and medicinal chemistry. The application of palladium on activated charcoal (Pd/C) as a heterogeneous catalyst was investigated for the carbonylation of 2-iodoanilines with trimethyl orthofor

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Pd/C as an Efficient Heterogeneous Catalyst for Carbonylative
Four-Component Synthesis of 4(3H)-Quinazolinones
Cite this: DOI: 10.1039/x0xx00000x
Kishore Natte, Helfried Neumann, and Xiao-Feng Wu*
Abstract: Quinazolinones are of interest in the fields of pharmaceuticals and medicinal chemistry.
The application of palladium on activated charcoal (Pd/C) as a heterogeneous catalyst was
investigated for the carbonylation of 2-iodoanilines with trimethyl orthoformate and amines via
multicomponent reaction approach in providing excellent yields of 4(3H)-quinazolinones. It avoids
the use of expensive phosphine ligands with an additional advantage of catalyst recovering.
Furthermore, >5 new quinazolinone scaffolds containing trifluoroethyl group were introduced by
this procedure and gram scale experiments were successfully performed as well.
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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Ever since the pioneering work of Heck and Schoenberg in 1974, generally suffering from low yields, multistep reactions, or relatively
palladium-catalyzed carbonylations have experienced impressive harsh reaction conditions. Therefore new methodologies for
progress during the past decades.1 By carbonylative transformations, quinazolinones synthesis are still under request.
CO, as one of the cheapest C1 source, can be incorporated into the
parent molecules and contribute to increasing the diversity of
As the above mentioned importance of carbonylations and
accessible compounds in many ways. With carbonylation reactions, quinazolinones, the application of carbonylation in quinazolinones
various carbonyl-containing compounds can be prepared easily, synthesis will be interesting. This idea has been realized by other
including valuable heterocycles. As heterocyclic compounds are chemists as well and many procedures have been reported. For
holding numerous applications in various areas, the integration of example, Willis and co-workers reported a straightforward procedure
cheap CO into valued heterocycles is like transform ‘stone’ into for the synthesis of quinazolinones with N-(o-halophenyl)-imidates as
‘gold’.2
their substrates.6 Alper’s group developed several carbonylative
procedures for quinazolinones synthesis based on N-(2-iodophenyl)-
N′-phenylcarbodiimides,7a o-iodoanilines and carbodiimides,7b or N-(2-
bromophenyl)pyridine-2-amines as the substares.8 Zhu and co-workers
succeeded in carbonylative synthesis of quninazolinones via C-H
activation.9,10 With N‑aryl-2-aminopyridines or N-arylamidines as the
starting materials, the corresponding quinazolinones were produced in
good yields. Our group developed several carbonylative procedures for
the preparation of quinazolinones as well.11 In the presence of
palladium catalyst; good yields of the desired products can be
produced. However, the discussed procedures are all homogeneous
palladium catalyst based, which have disadvantages include phosphine
ligands relied and not recyclable. Then Pd/C as a readily available
inexpensive heterogeneous catalyst comes into our interest.12 Here we
wish to report our new results on Pd/C-catalyzed carbonylative four-
component synthesis of 4(3H)-quinazolinones. With 2-iodoanilines,
trimethyl orthoformate and amines as the substrates, the desired
products were isolated in good to excellent yields. Notably, gram scale
and catalyst reuse experiments were performed successfully as well.
Initially, with 2-iodoaniline (1a), trimethyl orthoformate and
aniline (2a) in the presence of DiPEA as base as the reaction system,
various heterogeneous palladium catalysts were screened (Table 1,
entries 1, 8–10). Among them, (10%) Pd/C was found to be the best
catalyst providing an excellent yield of the desired product (Table 1,
entry 1). The same yield can be achieved even with 1 mol% of
Figure 1: Selected structures of biologically important quinazolinones
Among all the known heterocycles, quinazolinone core and its
derivatives consist an important class of compounds, as they are
existing in a large family of products with extensive biological
activities (Figure 1).3 They generally display useful therapeutic and
pharmacological properties such as anti-inflammatory, anti-
convulsant, antihypertensive and antimalarial activities.4 Due to the
wide range and applicability of quinazolinones and its related
derivatives, their synthesis has drawn interests from organic chemists.5
Among the developed procedures, most of the synthetic routes rely on
using anthranilic acid or its derivatives as the starting materials and
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palladium catalyst (Table 1, entry 5). However, the yield has been
relatively dropped with 0.5 mol% catalyst loading (Table 1, entry 6).
Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), trimethyl orthoformate
(2 mmol), base (3.0 mmol), solvent (3 mL), 110 °C, CO (10 bar), 20 h.
Table 1: Effect of catalyst on the palladium-catalyzed carbonylative
coupling of 2-idoanilines with amines, trimethyl orthoformate, and CO.[a]
With the optimized reaction conditions in the hand, we extended
this straight forward synthesis of 4(3H)-quinazolinones to a wider
range of amines and 2-iodoanilines (Table 3). As depicted in Table 3,
this 10% Pd/C catalytic system was surprisingly versatile. Structurally
diverse amines, including aromatic and aliphatic ones reacted with 2-
iodoaniline to give the desired products in good to excellent yields
(Table 3,entries 1–24).Various anilines, regardless of the presence of
electron-donating or electron-withdrawing groups reacted efficiently to
give 84–98% isolated yields of the desired products (Table 3, entries
1–9). Notably, trifluoromethyl group can be effectively installed into
the quinazolinone scaffolds by using trifluoroethyl amine as the
reaction partner as well (Table 3, entries 14-18).13 To the best of our
knowledge, these kind of quinazolinone compounds are scarcely
reported in the literature. To further demonstrate the general
applicability of this procedure, we then choose aniline as a standard
substrate to perform the reactions with different 2-iodoanilines. Both
electron-donating and electron-withdrawing substituents are tolerable
under the present reaction conditions (Table 3, entries 19–24).
However, no reaction occurred when 2-bromoaniline was applied as
the substrate. In the case of with strongly activated 3-amino-4-
bromobenzonitrile, still only trace of the desired quinazolinone was
detected.
Entry
Catalyst
3a Yield (%)[b]
1
2
Pd/C (5 mol%)
Pd/C (2.5 mol%)
Pd/C (2 mol%)
Pd/C (1.5 mol%)
Pd/C (1 mol%)
Pd/C (0.5 mol%)
-
96
94
3
94
4
94
5
94
6
87
7
No reaction
8
Pd/1,10 Phenonthroline
Pd/CeO2
22
56
44
9
10
Pd/TiO2
Reaction conditions: 2-Iodoaniline (1 mmol), aniline (1.2 mmol),
trimethyl orthoformate (2 mmol), DiPEA (3.0 mmol), toluene (3 mL), 110
°C, CO (10 bar), 20 h.
Then different solvents and bases were tested to show their effect
on this reaction. Solvents like acetonitrile, DMF, 1,4-dioxane, THF
DMSO and Xylene provided relatively lower yields of the expected
product (Table 2, entries 1-4, 6-7). Toluene was found to be the
optimal solvent (Table 2, entry 5) and used for further studies. In the
various tested organic and inorganic bases, no better yield can be
achieved than DiPEA (Table 2, entries 9-14). With the conditions in
entry 5 (Table 2), lower pressure of CO were tested; 80% of
quinazolinone can be formed under 5 bar of CO and the yield
decreased to 21% when perform the reaction under 1 bar of CO.
Given the importance of the 4(3H)-quinazolinone nucleus in many
natural products, we were interested to utilize our efficient synthetic
protocol for the synthesis of a pharmaceutically relevant alkaloids.
One such target with fundamental biological interest is
dihydrorutecarpin, a quinazolino carboline alkaloid which was used
for more than 2000 years in Chinese medical practice as a remedy for
gastrointestinal disorders (abdominal pain, dysentery), headache,
amenorrhea, and postpartum hemorrhage.14 By the present convergent
synthetic approach, carbonylative coupling of 2-iodoaniline and
trimethyl orthoformate with tryptamine under 10 bar of CO provides
3-[2-(3-indolyl)ethyl]-4(3H)-quinazolinone (24) in 88% yield (Scheme
1). The treatment of 24 with trifluoroaceticanhydride effected
cyclization to (trifluoroacetyl)-13b, l, 4-dihydrorutaecarpin, which can
be readily hydrolyzed to the desired dihydrorutaempine according to
the Bergman procedure.15 Additionally, we performed 1-g scale
reactions for selected substrates too. As shown in Scheme 2 in all these
cases we have obtained in excellent yields. Moreover, Pd/C was found
to be effectively recycled for four consecutive cycles in our recycling
experiments (Scheme 3).
Table 2. Optimization of palladium-catalyzed carbonylative coupling of
2-iodoanilines with amines, trimethyl orthoformate, and CO under
various reaction conditions.[a]
Entry
Base
Solvent
3a Yield (%)
1
2
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DiPEA
DBU
Acetonitrile
DMF
42
29
3
1,4 dioxane
THF
75
4
61
5
Toluene
DMSO
94
6
27
7
Xylene
90
8
H2O
No reaction
9
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
56
10
11
12
13
14
15
DABCO
TEA
64
81
K2CO3
Cs2CO3
Na2CO3
-
45
59
41
No reaction
2 | J. Name., 2012, 00, 1-3
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Scheme 3: Recyclability study of Pd/C catalyst.
Scheme 1: Palladium-catalyzed four-component carbonylative coupling reaction for
the synthesis of dihydrorutecarpin.
In summary, we have developed a relatively mild, operationally
simple, phosphine-free and recyclable catalytic system for the
carbonylative synthesis of 4(3H)-quinazolinones. With 2-iodoanilines,
trimethyl orthoformate, and amines as the substrates, the desired
quinazolines were formed in good to excellent yields. Additionally,
gram scale and catalyst reuse experiments were performed
successfully as well.
Scheme 2: Gram scale reactions.
Table 3: Palladium-catalyzed carbonylative coupling of various amines with 2-iodoanilines, trimethylorthoformate, and CO
Entry
1
2-iodoaniline
Amine
Product
Yield[b]
97
2
3
98
96
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4
93
5
6
7
91
97
93
8
84
9
87
95
10
11
12
13
90
98
98
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14
15
16
17
18
96
97
93
96
98
19
20
97
93
21
22
23
96
98
95
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24
91
Reaction conditions: 2-iodoaniline or substituted 2-iodoaniline (1 mmol), amine (1.2 mmol), trimethyl orthoformate (2 mmol), DiPEA (3.0 mmol),
toluene (3 mL), 110 °C, CO (10 bar), 20h.
General information
E-Mail: xiao-feng.wu@catalysis.de
Reactions were run under an argon/N2 atmosphere with exclusion of
moisture from reagents and autoclaves. All substrates were purchased
from Sigma–Aldrich, were used as received. Solvents were dried from
molecular sieves and kept under argon. NMR spectra were recorded on
the Bruker AV 300 spectrometers. All chemical shifts (δ) are reported
in parts per million (ppm) and coupling constants (J) in Hz. All
chemical shifts are reported relative to tetramethylsilane (δ 0.0 for 1H
NMR in DMSO-d6, CDCl3) and d-solvent peaks (δ 77.00 for 13C
NMR, chloroform and for DMSO-d6, δ 40.00), respectively. All
measurements were carried out at room temperature unless otherwise
stated. Mass spectra were recorded on an AMD 402/3 or a HP 5989A
mass selective detector. Gas chromatographic analysis was performed
on an Agilent HP-5890 instrument with an FID detector and an HP-5
capillary column (poly(dimethylsiloxane) with 5% phenyl groups, 30
m, 0.32 mm i.d., 0.25 mm film thickness) with argon as the carrier gas.
The chemicals are ordered from Aldrich.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
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Experimental section
A 12 mL vial was charged with 10 wt. % Pd/C (1 mol%; 10 mg), 2-
iodoaniline (1 mmol) and a stirring bar. Then, aniline (1.1 mmol),
trimethyl orthoformate (2 mmol), DiPEA (3 mmol), and toluene (3
mL) were injected by syringe under argon. The vial (or several vials)
was placed in an alloy plate, which was transferred into a 300 mL
autoclave of the 4560 series from Parr Instruments® under argon
atmosphere. After flushing the autoclave three times with CO, a
pressure of 10 bar CO was adjusted at ambient temperature. Then, the
reaction was performed for 20 h at 110 oC. After the reaction finished,
the autoclave was cooled down to room temperature and the pressure
was released carefully. The solution was filtered through whatmann
filter paper and washed the reaction mixture with acetone (2-3 ml).
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silica gel and the crude product was purified by column
chromatography using n-heptane/ethyl acetate (7:3) as eluent.
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We thank the state of Mecklenburg-Vorpommern and the
BundesministeriumfürBildung und Forschung (BMBF) for financial
support. We also thank Dr. W. Baumann, Dr. C. Fischer, and S.
Buchholz (LIKAT) for analytical support. The general supports from
Prof. Matthias Beller are acknowledged.
Notes and references:
Leibniz-Institut für Katalyse an der Universität Rostock, Albert-
Einstein-Straße 29a, 18059 Rostock (Germany)
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A relatively mild, operationally simple, phosphine-free and
recyclable catalytic system for the carbonylative synthesis of
4(3
H
)-quinazolinones
with
2-iodoanilines,
trimethyl
orthoformate, and amines as the substrates has been
developed.
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