Gold(0) catalyzed dehydrogenation of N-heterocycles

Article abstract of DOI:10.1016/j.tetlet.2018.09.050

Gold nanoclusters are good catalyst precursors for the catalytic dehydrogenation of indolines, tetrahydroquinazolines, and related N-heterocycles. The catalytically active species is presumably Au(0) nanoparticles.

Full text of DOI:10.1016/j.tetlet.2018.09.050

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Gold(0) Catalyzed Dehydrogenation of N-Heterocycles
Kumaran Elumalai, Weng Kee Leong
PII:
S0040-4039(18)31149-3
https://doi.org/10.1016/j.tetlet.2018.09.050
TETL 50289
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Reference:
Tetrahedron Letters
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18 September 2018
Please cite this article as: Elumalai, K., Leong, W.K., Gold(0) Catalyzed Dehydrogenation of N-Heterocycles,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.050
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Tetrahedron Letters
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Gold(0) Catalyzed Dehydrogenation of N-Heterocycles
Kumaran Elumalai, and Weng Kee Leong*
aDivision of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371. e-mail: chmlwk@ntu.edu.sg
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Gold nanoclusters are good catalyst precursors for the catalytic dehydrogenation of indolines,
tetrahydroquinazolines, and related N-heterocycles. The catalytically active species is
presumably Au(0) nanoparticles.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Gold
Catalytic dehydrogenation
Indoles
Quinazolines
1. Introduction
Indoles are one of the most widely distributed heterocyclic compounds in Nature, with many indole alkaloids possessing
considerable pharmacological activity.1 Indoles also feature in agricultural and animal health products, textiles, and perfumes.2 For
these reasons, the synthesis of indole ring derivatives continues to be of interest to synthetic chemists.3 Among the synthetic
methodologies available, the direct dehydrogenation of indolines to indoles is a promising route towards a wide variety of indole
derivatives.4 Indoline dehydrogenation has been achieved via electrochemical oxidation,5 and has also been shown to be catalyzed by a
number of transition metals, such as, ruthenium6 and palladium.7 More generally, the dehydrogenation of other N-heterocycles has been
studied with metal complexes based on iron,8 cobalt,9 nickel,10 and iridium,11 among others.12
Following the work of Angelici and co-workers on the use of bulk gold powder (~103 nm particle size) as a catalyst for the aerobic
oxidative dehydrogenation of secondary amines to imines, and the fact that this catalytic oxidation likely occurred on the active surface
of the heterogeneous gold powder,13 there has been several reports on gold-catalyzed amine dehydrogenation.14 Nevertheless, reports on
the gold catalysis of indoline dehydrogenation has been sparse, and they include the use of Au(OAc)3 supported on CeO2,15 and KAuCl4
supported on graphite,16 as precursors to active gold nanoparticles. Extension of this reaction to substituted indolines or other N-
heterocycles has also not been explored. The recent surge in interest regarding thiolate-protected gold nanoclusters led us to consider
whether they could be utilized in the catalytic dehydrogenation of indolines. In this study, we have examined a number of thiolate- and
the earlier-known phosphine-protected gold nanoclusters in the catalytic dehydrogenation of indoline (Table 1).
Table 1. Optimization study for the oxidative dehydrogenation of indoline.
Catalyst
Oxidant
Entry
Yield 3a (%)a
Catalyst (mol%)
Oxidant (1.2 eq.)
air
Toluene
N
N
100 oC, 20 h
1
2
3
4
5
6
7
8
9
10
1 (1)
-
H
H
1 (1)
pyridine-N-oxide
H2O2
22
74
93
-
3a
2a
1 (1)
1 (1)
TMNO
TMNO
-
-
1 (1)
-
1 (0.5)
TMNO
TMNO
TMNO
TMNO
55
60b
50
23
1 (1)
PPh3AuCl (10)
Au25(S-hex)18 (1)

[Au25(SC2H4Ph)18]- (1)
TMNO
TMNO
TMNO
TMNO
21
75
a NMR yield. b 50 °C. c 60 °C in THF. d 80 °C in MeCN or DCE.
11
12
13
14
[Au11(PPh3)8Cl2]Cl (1)
No oxidation occurred when indoline 2a was heated in air to 100
°C with a catalytic amount (1 mol%) of Au11(PPh3)8Cl3 1 (Entry 1),
but the reaction proceeded in the presence of an added oxidant
(Entries 2-4), with TMNO giving the best performance. Control
c
1 (1)
1 (1)
-
d
-
experiments showed that both 1 and an oxidant were necessary (Entries 5 and 6), and reducing the amount of catalyst or lowering the
temperature led to lower yields (Entries 7 and 8). The Au(I) complex PPh3AuCl and two thiolate-protected gold nanoclusters showed
significantly poorer performance (Entries 9-11), while the cationic form of 1, viz., [Au11(PPh3)8Cl2]Cl showed slightly poorer
performance (Entry 12). The reaction failed to proceed in solvents such as tetrahydrofuran, 1,2-dichloroethane and acetonitrile.
Monitoring the reaction by 31P{1H} NMR spectroscopy showed that the resonance for 1 at 54 ppm was replaced by a new resonance for
Ph3PO at 25 ppm after 1 h, and this remained until reaction completion.
The above observation, together with the results in Table 1, suggests that the active catalyst is probably Au(0) nanoparticles. Indeed,
the reaction profile for indoline with 1 as the catalyst shows an induction period of about an hour, consistent with the decomposition of
1 into nanoparticles and hence heterogeneous catalysis (Fig. 1). Phosphine-protected gold nanoclusters having a higher proportion of
R
Au(0) than the thiolate-protected gold nanoclusters may account for
R
Au11(PPh3)7Cl3 (2 mol%)
the better performance of the former as they form Au(0)
TMNO (2.4 eq.)
Toluene
N
N
nanoparticles more readily.
100 oC, 20 h
H
5
4
Figure 1. Reaction profile for the oxidative dehydrogenation of
indoline catalyzed by 1. Reagents and conditions: indoline (0.2
mmol), 1 (1 mol%), TMNO (0.24 mmol), toluene-d8, 100 °C. 1,3,5-
5a
5b
5c
R= H ( ,85%), 6-Br ( , 77%), 6,8-Br ( , 45%)
Au11(PPh3)7Cl3 (2 mol%)
TMNO (2.4 eq.)
N
NH
N
Toluene
100 oC, 20 h
5d'
, 70%
4d
5d
,13%
trimethoxybenzene was used as an internal standard to determine
conversion.
A substrate scope study using 1 with the optimized conditions
proceeded well with indolines possessing a variety of functional
groups (Table 2). With 1,2,3,4-tetrahydroquinolines, 2 mol% of 1 and
2.2 equivalents of TMNO were required for reaction completion,
while under similar conditions, 1,2,3,4-tetrahydroisoquinoline
afforded a mixture of isoquinoline and 3,4-dihydroisoquinoline in
13% and 70% yield, respectively (Scheme 1).
Table 2. Substrate scope for the oxidative dehydrogenation of
indolines.
N
Scheme 1. Oxidative dehydrogenation of 1,2,3,4-
tetrahydroquinolines and 1,2,3,4-tetrahydroisoquinoline.
CHO
Au11(PPh ) Cl (1 mol%)
NH2
3 7
3
N
R1
R1
TMNO (1.2 eq.)
NH2
H C
Tolu3ene
R2
N
R7c2
, 71%
N
The latter reaction conditions also led to the dehydrogenation
CH3
100 oC, 20 h
H
H
Entry
R1
R2
Product (% isolated yield)
of
3
2
1,2,3,
1
2
3
4
5
6
7
8
9
H
H
3a (79)
4-tetrahydroquinazolines to quinazolines in good yields (Table 3); substituted
5-CH3
5-Br
5-F
5-NO2
6-NO2
H
H
3b (89)
quinazolines have potential therapeutic effects.17
H
3c (75)
H
3d (86)
Table 3. Substrate scope for the oxidative dehydrogenation of 1,2,3,4-
H
3e (87)
tetrahydroquinazolines.
H
3f (71)
CH3
3g (78)
NH
N
H
CO2CH3
CO2C2H5
3h (85)
N
R
N
R
H
3i (83)
H
6
7

Entry
R
Product (% isolated yield)
7a (78)
Reagents and conditions: cluster 1 (2 mol%), TMNO (2.4 eq.), toluene,
°C, 20 h.
100
the
1
2
3
4
5
6
7
8
9
H
C6H5
7b (76)
Quinazolines are also obtainable via a one-pot reaction, as exemplified by
reaction of 2-aminobenzylamine with 4-methylbenzaldehyde to give 2-(p-
tolyl)quinazoline, 7c in good yield (Scheme 2).
CH3-4-C6H4
MeO-4-C6H4
CN-4-C6H4
Cl-4-C6H4
NO2-4-C6H4
MeO2C-4-C6H4
Furan-2-yl
7c (87)
7d (92)
Scheme 2. One-pot reaction to synthesize quinazolines.
7e (91)
A
7f (92)
mechanism involving surface Au+ sites has been proposed for the selective
oxidation of amines by Au nanoparticles.16 An alternative, depicted in Figure
indoline 2a, involves oxidative addition of the indoline N-H bond across an
unit leading to intermediate A. This can then undergo β–hydrogen
elimination to give B and the hydrido digold species C. Intermediate B
undergoes tautomerization to the indole, whereas C reacts with TMNO to
7g (90)
2 for
Au2
7h (93)
7i (82)
regenerate the two Au(0) centres. This pathway parallels that proposed for amine oxidation over the intermetallic Pd3Pb surface.18
Me3N + H2O
Au-Au
Figure 2. Proposed catalytic cycle for the 1-catalyzed
dehydrogenation of indoline.
N
H
In conclusion, we have found that gold nanoclusters are good
catalyst precursors for Au(0) nanoparticles which catalyse the
dehydrogenation of indolines, tetrahydroquinazolines, and related N-
heterocycles.
Me3NO
Removal of
H-atoms
Adsorption &
N-H activation
H
H
Au-Au
N
H
Acknowledgments
A
Au-Au
C
This work was supported by a research grant (SERC grant no.
1521200076) from the Agency for Science, Technology and Research
(A*STAR), Singapore.
C-H activation &
desorption
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Supplementary Material
Details of experiments and characterization data of all products.
Highlights



Gold nanoclusters as pre-catalysts
Gold nanoparticles as catalysts
Catalytic oxidative dehydrogenation of N-heterocycles under mild conditions