Direct and co-catalytic oxidative aromatization of 1,4-dihydropyridines and related substrates using gold nanoparticles supported on carbon nanotubes

Article abstract of DOI:10.1039/c6cy00453a

A heterogeneous catalyst was assembled by stabilization of gold nanoparticles on carbon nanotubes. The resulting nanohybrid was used in the catalytic aerobic oxidation of 1,4-dihydropyridines. The system proved very efficient on the investigated substrates either directly or in the presence of a quinone co-catalyst.

Full text of DOI:10.1039/c6cy00453a

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Direct and co-catalytic oxidative aromatization of 1,4-
dihydropyridines and related substrates using gold nanoparticles
supported on carbon nanotubes†
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
c
d
DOI: 10.1039/x0xx00000x
Praveen Prakash, Edmond Gravel, Haiyan Li, Frédéric Miserque, Aurélie Habert, Martien den
e
f
,g
,a
Hertog, Wai Li Ling, Irishi N. N. Namboothiri,* and Eric Doris*
www.rsc.org/
A heterogeneous catalyst was assembled by stabilization of gold However, the oxidation of dihydropyridines is not always easy
nanoparticles on carbon nanotubes. The resulting nanohybrid was when substrates bear sensitive functional groups and there is
used in the catalytic aerobic oxidation of 1,4-dihydropyridines. still the quest for mild and general protocols. Also, some of the
The system proved very efficient on the investigated substrates reported procedures lead to the formation of by-products
either directly or in the presence of a quinone co-catalyst.
which can be difficult to remove from the reaction mixture.
Therefore, the development of milder, sustainable, and more
effective methods for the oxidative aromatization of 1,4-
dihydropyridines is sound. In the present article, we report the
assembly and use of a recyclable CNT-supported gold catalyst
for the selective and mild aerobic oxidation of 1,4-
dihydropyridines and related substrates (Figure 1).
Pyridines have found applications in various domains such as
1
2
3
in the synthesis of drugs, herbicides, or insecticides. In
addition, the pyridine scaffold plays a central role in living
systems
since
nicotinamide
adenine
dinucleotide
+
NAD /NADH) and nicotinamide adenine dinucleotide
(
+
phosphate (NADP /NADPH) are key pyridine-incorporating co-
4
factors involved in oxido-reduction processes. Among the
various methods developed for the synthesis of pyridine
5
derivatives, the oxidation of Hantzsch 1,4-dihydropyridines is
likely one of the most straightforward approaches. The
Hantzsch pyridine synthesis is a multi-component process
which involves an aldehyde, two equivalents of a β-keto ester,
and a nitrogen atom source. The initial condensation affords a
dihydropyridine intermediate which can be oxidized, in a
second step, into the corresponding pyridine. This reaction
6
was reported for the first time in 1881 by Arthur Hantzsch.
Numerous reagents have been reported to promote the
second step-oxidative aromatization reaction and include, for
7
example, copper bromide, ferric chloride, palladium on
8
9
carbon, manganese dioxide, and tert-butylhydroperoxide.
10
11
Figure 1 Overview of the catalytic assembly and catalyzed oxidation processes studied
in the present work.
The CNT-gold catalyst was assembled using a layer-by-layer
approach according to a previously reported procedure from
1
2
our group. Our strategy relied on the use of specific
amphiphiles which are made of a nitrilotriacetate polar head
and a C25-diacetylene lipophylic chain. This amphiphile can
spontaneously self-assemble in water on the CNT to yield
hemi-micellar structures having lipophylic chains in interaction
with the CNT and polar heads oriented towards the aqueous
medium. This primary layer provides a dense anionic covering
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of the nanotube that is not dependent on the presence of the Gold concentration of the aqueous suspension was assessed
carboxylic defects on the CNT surface, unlike most strategies by ICP-MS ([Au] = 3.4 mM), and the metallic nature of gold
1
3
classically designed for the decoration of carbon nanotubes.
The diacetylene motif of the amphiphiles also allowed further S4). The presence of the metallic species on the CNT surface
stabilization of the supramolecular assembly through was further evidenced by energy dispersive X-ray analysis
evidenced by X-ray photoelectron spectrometry (XPS, Figure
a
polymerization process triggered by UV irradiation at 254 nm. (EDX, Figure S5) and thermogravimetric analysis (TGA, Figure
After photopolymerization the coating becomes robust and S6) which revealed that the nanohybrid had a gold content of
withstands ethanol washings which is not the case of the non- ca. 25 wt%.
polymerized equivalent. The negatively charged CNT surface is
With the CNT-gold nanohybrid in hands, we next looked at
then used for the deposition of the second layer composed of its performances in the catalytic oxidation of various 1,4-
a cationic polymer (polydiallyldimethyl ammonium chloride) dihydropyridines. Standard oxidation reaction conditions were
which is immobilized through electrostatic interactions. This set using 1,4-dihydropyridine 1a as model substrate in the
polymer provides a tridimensional network that is capable of presence of 0.5 mol% of the catalyst, in CHCl
3 2
/H O under air.
accommodating and stabilizing pre-formed gold Under these conditions, 97% of pyridine 2a was produced in
1
4
nanoparticles that are finally added to the multilayered 24 h (Table 1, Entry 1). Changing the air atmosphere for pure
nanotube to afford the AuCNT nanohybrid catalyst. The above oxygen permitted to increase the reaction rate as pyridine 2a
procedure led to carbon nanotubes uniformly covered with was obtained in nearly quantitative yield (99% conversion) in
gold nanoparticles of ca. 3 nm of diameter, as visualized by only 11 h (Entry 1). It was thus decided to perform the ensuing
transmission electron microscopy (Figure 1 and Figure S3).
experiments under an oxygen atmosphere. To assess the
scope of the process, the conversion of several other 2,3,5,6-
tetrasubstituted dihydropyridines into the corresponding
pyridines was studied (Entries 2-5). Diketone derivative 1b
Table 1 Scope of the AuCNT-catalyzed oxidation of 1,4-dihydropyridines and
a
polyhydroquinoline.
(
Entry 2), di-allylester derivative 1c (Entry 3), and DHP 1d
bearing ethyl groups in positions 2 and 6 (Entry 4) were all
converted into the corresponding pyridines (2b 2c, and 2d
,
,
respectively) in excellent yields under the action of the AuCNT
hybrid. The oxidation of unsymmetrical bicyclic compound 1e
(
Entry 5) was quantitative after 36 h of reaction but required
t
Yldb
Entry
1
Substrate
1
Product
2
the use of 1 mol% of the catalyst.
(h) (%)
Although efficient on 1,4-dihydropyridines that are not
substituted at the 4-position, the direct AuCNT-catalyzed
oxidation failed on the phenyl-substituted 1,4-dihydropyridine
c
2
1
4
1
97
99
1a
2a
1f (Entry 6), even with extra catalyst loading (e.g. 1 mol%).
Nevertheless, we conceived that the use of a quinone co-
catalyst could help to achieve the expected transformation,
1
5
2
3
1b
1c
2b
2c
14 99
18 96
since redox-active quinones are known oxidants of 1,4-DHPs.
Thus, the combination of a quinone co-catalyst together with
AuCNT could provide the answer to the observed inertness of
some of the 1,4-DHP-substrates. The quinone unit would
catalyze the aromatization reaction of 4-substituted 1,4-DHPs
while the supported gold particles achieve the in situ re-
oxidation of the released hydroquinone, hence completing the
d
1
6
catalytic cycle (Scheme 1).
4
5
1d
1e
1f
2d
2e
2f
18 98
36 99
e
Scheme 1 Proposed strategy for the co-catalytic oxidative aromatization of 1,4-
dihydropyridines.
e
6
-
36 NR
Various quinone derivatives (Figure 2) were screened in the
co-catalytic oxidative aromatization of 1,4-DHP 1f under
oxygen atmosphere. Thus, 1,4-DHP 1f was reacted with 1
a
Reaction conditions: dihydropyridine
1
(0.1 mmol), AuCNT (0.5 mol%),
b
c
d
e
CHCl
3 2 2
/H O (3:1, 2 mL), O . Isolated yields. under air. In methanol (2 mL).
mol% of AuCNT in CHCl
of a co-catalyst (either
gallacetophenone ( ) or 4-tert-butylcatechol (
3
/H
2
O and in the presence of 20 mol%
, or ). While the use of
) as co-catalysts
AuCNT (1 mol%).
3
,
4
5
3
4
2
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provided only poor to moderate yields of the aromatized
Additional examples of 4-substituted dihydropyridines
pyridine 2f after 36 h of reaction (ca. 5% and 40% yield, were studied using the co-catalytic system (Table 2, Entries 2–
respectively), the use of 2,5-dichloro-1,4-benzoquinone ( 5). Dihydropyridines substituted by various aromatic groups at
gratifyingly afforded the expected pyridine 2f in 78% yield the 4-position were successfully oxidized to the corresponding
Table 2, Entry 1). A blank experiment conducted under the pyridines in satisfactory to good yields (from 45 to 84%). It
same conditions (20 mol% of ) but in the absence of AuCNT appeared that compounds bearing electron-rich aromatics at
5)
(
5
led only to 14% conversion of 1f into 2f. This result highlights the 4-position (Entries 2) seemed to react more readily than
the cooperative contribution of the two co-catalysts that substrates incorporating electron withdrawing groups (Entry
synergistically catalyzed the oxidative aromatization reaction.
3). The reaction worked equally well on the DHP 1i which is
substituted with an aliphatic methyl group (Entry 4) but was
more sluggish on furanyl derivative 1j whose pyridine
counterpart 2j was produced in 45 % yield (Entry 5). It is to be
noted that reaction times were in general higher in the case of
4
-substituted DHPs compared to their non-substituted
counterparts. Yet, our AuCNT system compares favorably with
a previously reported polymer-supported platinum catalyst
which required a co-factor for non-substituted (at the 4-
Figure 2 Structures of investigated co-catalysts.
1
7
position) DHP substrates.
a
Recyclability of the AuCNT nanohybrid was evaluated over
five consecutive oxidation reactions of 1a using the same
batch of the catalyst which was recovered by simple
centrifugation after each cycle. The catalytic activity remained
the same throughout the experiment as the pyridine derivative
Table 2 Scope of the AuCNT-catalyzed oxidation of 3-substituted 1,4-dihydropyridines.
2
a
was obtained in each case in nearly quantitative yields
Table 3). TEM analysis after the fifth run showed no significant
Yld alteration of the nanohybrid catalyst.
(
t
(
Entry
1
Substrate
1
Product
2
b
h) (%)
a
Table 3 Recycling experiments of the AuCNT catalyst.
1f
2f
36 78
b
2
1g
2g
44 84
Entry
Cycle
Fresh
Yld (%)
1
2
3
4
99
st
1 Reuse
98
nd
2
3
4
Reuse
Reuse
Reuse
99
rd
th
97
3
4
1h
2h
48 55
5
98
a
Reaction conditions: dihydropyridine 1a (0.1 mmol), AuCNT (0.5 mol%),
b
3 2 2
CHCl /H O (3:1, 2 mL), O . Isolated yields.
1i
1j
2i
2j
54 82
Conclusions
A heterogeneous catalyst was assembled by stabilization of
gold nanoparticles on carbon nanotubes via a layer-by-layer
approach. The resulting nanohybrid was used in the catalytic
aerobic oxidation of 1,4-dihydropyridines under very mild
conditions (room temperature, atmospheric pressure). The
gold-CNT assembly proved very efficient on its own for the
oxidation of 2,3,5,6-tetrasubstituted dihydropyridines and was
also active, in combination with a quinone co-catalyst, for the
oxidation of 2,3,4,5,6-pentasubstituted dihydropyridines. The
5
48 45
a
Reaction conditions: dihydropyridine 1 (0.1 mmol), AuCNT (1 mol%), 5 (20
b
3 2 2
mol%), CHCl /H O (3:1, 2 mL), O . Isolated yields.
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heterogeneous nature of the catalyst enabled its recycling and
reuse with no loss of activity.
Supports from the Indo-French Centre for the Promotion of
Advanced Research (IFCPAR) / Centre Franco-Indien pour la
Promotion de la Recherche Avancée (CEFIPRA) (Project no.
4705-1) and from the Enhanced Eurotalents program are
gratefully acknowledged. The TEM-team platform (CEA, iBiTec-
S) is acknowledged for help with TEM images. The “Service de
Chimie Bioorganique et de Marquage” belongs to the
Laboratory of Excellence in Research on Medication and
Innovative Therapeutics (ANR-10-LABX-0033-LERMIT).
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