Hydrogenation or Dehydrogenation of N-Containing Heterocycles Catalyzed by a Single Manganese Complex

Article abstract of DOI:10.1021/acs.orglett.0c01273

A highly chemoselective base-metal catalyzed hydrogenation and acceptorless dehydrogenation of N-heterocycles is presented. A well-defined Mn complex operates at low catalyst loading (as low as 2 mol %) and under mild reaction conditions. The described catalytic system tolerates various functional groups, and the corresponding reduced heterocycles can be obtained in high yields. Experimental studies indicate a metal-ligand cooperative catalysis mechanism.

Full text of DOI:10.1021/acs.orglett.0c01273

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Letter
Hydrogenation or Dehydrogenation of N‑Containing Heterocycles
Catalyzed by a Single Manganese Complex
Viktoriia Zubar, Jannik C. Borghs, and Magnus Rueping*
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ABSTRACT: A highly chemoselective base-metal catalyzed
hydrogenation and acceptorless dehydrogenation of N-heterocycles
is presented. A well-defined Mn complex operates at low catalyst
loading (as low as 2 mol %) and under mild reaction conditions.
The described catalytic system tolerates various functional groups,
and the corresponding reduced heterocycles can be obtained in
high yields. Experimental studies indicate a metal-ligand cooperative catalysis mechanism.
ransition-metal-catalyzed hydrogenation of polar bonds is
a well accepted and widely used method for the synthesis
Recently, an increasing number of reports featuring the high
reactivity of Mn complexes for the hydrogenation of aldehydes,
ketones, nitriles, esters, and amides have been published.14−23
More challenging substrates such as organic carbonates,
carbamates, and urea derivatives could also be hydrogenated
using manganese complexes.24−27 To the best of our
knowledge, only a few reports addressing the reduction of
heteroaromatic systems have been published.28−31 Based on
our interest in manganese catalysis as well as hydrogenations
and dehydrogenations, we decided to explore the hydro-
genation of indoles as representatives of N-heterocyclic
compounds. The indole scaffold is considered to be one of
the most important organic frameworks for the discovery of
new drugs as many of the indole derived compounds play a
significant role in nature. Among them are tryptophan, an α-
amino acid which is essential to humans, the neurotransmitter
serotonin, and melatonin, a hormone which regulates the
sleep−awake cycles. The indoline skeleton is equally
important, and it is found in numerous bioactive compounds,
pharmaceuticals, herbicides, and insecticides.32,33 Hydrogena-
tion of indoles is a difficult task due to the high stability of the
aromatic heterocyclic ring. Among the conventional methods
to achieve saturated heterocycles we may highlight the use of
NaBH3CN. It is one of the most used methods, however, due
to the use of superstoichiometric amounts of the hydride
source and the generation of high amounts of waste, such as
cyanides, and other improved systems are still desired.
T
of a diverse set of value-added products such as alcohols,
amines, saturated heterocycles, etc.1 However, most of the
reports focus on using rare and expensive transition metals or
heterogeneous catalysts, which may require harsh reaction
conditions resulting in a low functional group tolerance. The
replacement of noble metals by sustainable base metals is
currently getting increased attention due to their lower toxicity
and ubiquitous abundance.2 On the other hand, saturated and
unsaturated heterocycles are considered as liquid organic
hydrogen carriers (LOHC) due to their reversible dehydrogen-
ating properties. Using N-containing heterocycles as LOHC
allows the avoidance of problems associated with commonly
studied LOHC reagents including ammonia borane, sodium
borohydride, and metal hydrides. First, they are abundant and
economically advantageous. Second, the dehydrogenation
process for these molecules is endothermic, which prevents
uncontrolled thermal reactions. Thus, N-containing hetero-
cycles are considered to be a good alternative if compared to
hydrocarbons due to the lower energy barrier for de-/
hydrogenation processes.3−5 Examples of a single catalyst
which are able to catalyze both the hydrogenation and
dehydrogenation process are very rare in the literature.
Zhou, Li, and co-workers6 as well as Fujita and co-workers7
studied iridium complexes for this transformation. Later,
Crabtree and co-workers8 and Albrecht and co-workers9
reported the use of iridium complexes for the catalytic
hydrogenation and dehydrogenation of N-heterocycles in
water. In addition, Fischmeister and co-workers reported a
mild reversible hydrogenation of quinoline derivatives using an
iridium-based catalyst.10 Although the field is dominated by
the application of iridium catalysts, Jones and co-workers
focused on using base metals such as Fe11 and Co12 for this
transformation.13 However, Mn-based systems remain un-
known. Therefore, the development of single catalysts for the
reversible dehydrogenation process is interesting and desired.
The catalytic hydrogenation using hydrogen gas as the
reducing agent is an attractive process due to the low cost of
Received: April 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01273
© XXXX American Chemical Society
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a
hydrogen, atom economy, and minimal waste generation.
Encouraged by our previous results, we were interested to find
out whether a bench-stable Mn−PNP catalyst would be active
enough for the hydrogenation of N-containing heterocyclic
compounds. Simple unsubstituted indole 1a was chosen as a
model substrate to test the above-mentioned reaction. We
were pleased to see that indoline 2a was formed in high yield
(85%) upon running the reaction for 24 h at 100 °C, 50 bar of
H2, with 2 mol % of the catalyst and 5 mol % of base (Table 1,
Scheme 1. Manganese-Catalyzed Hydrogenation of Indoles
a
Table 1. Optimization of the Reaction Conditions
b
entry
[Mn-1] (mol %)
base (mol %)
solvent
yield (%)
c
1
Mn-1(2)
KOtBu (5)
KOtBu (5)
KOtBu (5)
KOtBu (5)
CsOH·H2O (5)
Cs2CO3 (5)
K3PO4 (5)
NaOtBu (5)
KOtBu (2.5)
KOtBu (5)
toluene
TAA
85
57
18
92
92
88
36
71
47
nd
c
2
Mn-1 (2)
Mn-1 (2)
Mn-1 (2)
Mn-1 (2)
Mn-1 (2)
Mn-1 (2)
Mn-1 (2)
Mn-1 (1)
Mn(CO)5Br (2)
c
3
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
4
5
6
7
8
9
10
a
Reaction conditions: indole 1a (0.25 mmol), [Mn], base in 1 mL of
b
solvent at 100 °C under 50 bar of H2 for 36 h. Determined by GC
analysis using dodecane as internal standard. Reaction time is 24 h.
c
TAA = tert-amyl alcohol.
entry 1). The yield did not increase when the reaction was
performed in polar protic tert-amyl alcohol and polar aprotic
dioxane as solvent (Table 1, entries 2 and 3). Increasing the
reaction time to 36 h led to indoline 2a in 92% yield (Table 1,
entry 4). Using CsOH·H2O instead of KOtBu provided the
product with the same efficiency (Table 1, entry 5). The
application of other bases did not improve the reaction
outcome (Table 1, entries 6−8). Decreasing the catalyst
loading to 1 mol % resulted in 47% yield of indoline only
(Table 1, entry 9). The application of Mn(CO)5Br precursor
in the reaction resulted in the full recovery of the indole (Table
1, entry 10), which highlights the crucial role of the ligand.
In order to demonstrate the potential and applicability of the
newly developed catalytic hydrogenation system, a range of
substituted indoles 1a−1o were tested under the optimized
reaction conditions (Scheme 1). Different substituted indoles
were efficiently and selectively hydrogenated to the corre-
sponding indolines with good to very good yields. Simple
substituted indoles with methyl groups in the C-6 and C-7
positions were also well tolerated and led to the desired
products 2b and 2c in very good yields. An elevated
temperature was needed when 5-methoxyindole was applied
in the reaction, resulting in 85% of the corresponding indoline
2d. Remarkably, methylindole-5-carboxylate was selectively
hydrogenated, yielding the desired indoline in 97% yield, with
the ester group remaining intact.
a
Reaction conditions: 1 (0.25 mmol), Mn-1 (2 mol %) and KOtBu (5
mol %) in toluene (1 mL) at 100 °C under 50 bar of H2 for 36 h.
b
Isolated yields are provided. Yields for scale-up experiment (2.5
c
d
mmol of starting material used). 130 °C. Mn-1 (5 mol %) and
KOtBu (12.5 mol %).
reaction conditions. Scale-up experiments were performed
resulting in high yields of the corresponding indolines.
Quantitative yields were observed for the substrates 1e, 1f,
and 1h which indicates the high potential of this trans-
formation. In addition, the hydrogenation of C3-substituted
indoles could be performed. The application of an elevated
reaction temperature (130 °C) and a higher catalyst loading (5
mol %) were required for the reaction to proceed successfully.
To the best of our knowledge, manganese-catalyzed reduction
of C3-substituted indoles using molecular hydrogen was not
yet reported.
In addition to indoles, other different N-containing hetero-
cycles could be applied in the transformation (Scheme 2).
Unsubstituted and substituted quinoxalines 3a−c as well as
benzoxazine 3d were successfully applied in the reaction
resulting in quantitative yields of the corresponding products.
Considering the above results we decided investigate
whether a manganese-catalyzed dehydrogenation would also
be accessible, demonstrating for the first time the applicability
Halogen-containing substrates were also tolerated, resulting
in high yields for the products 2f−2i. It is worth mentioning
that no hydrodehalogenation occurred under the optimized
B
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The proposed catalytic cycle for the hydrogenation of indole
and dehydrogenation of indoline is depicted in Scheme 4. The
Scheme 2. Manganese-Catalyzed Hydrogenation of N-
Containing Heterocycles
a
Scheme 4. Proposed Reaction Mechanism of Reversible
Indole Hydrogenation and Dehydrogenation Using Mn-1
Complex
a
Reaction conditions: 3 (0.25 mmol), Mn-1 (1 mol %), and KOtBu
(2.5 mol %) in toluene (1 mL) at 120 °C under 50 bar of H2 for 24 h.
b
c
Isolated yields are provided. 140 °C. Mn-1 (2 mol %) and KOtBu
d
(5 mol %). Mn-1 (3 mol %) and KOtBu (7.5 mol %).
of manganese complexes in both hydrogenation and
dehydrogenation reactions. Thus, we started to investigate
the applicability of Mn-1 to catalyze the dehydrogenation of
other N-containing heterocycles under oxidant-free conditions
(Scheme 3). To our delight, indoline was successfully
first step for the hydrogenation process is the activation of Mn-
1 using the base (KOtBu) and formation of an active species A.
Next, species A reacts with hydrogen to form H−N−Mn−H
species B, which successfully hydrogenates indole to indoline.
The dehydrogenation reaction begins also with the formation
of an active species A, which dehydrogenates indoline to indole
and becomes species B, which releases a hydrogen molecule
afterward.
Scheme 3. Manganese-Catalyzed Dehydrogenation of N-
a
Containing Heterocycles
In order to support the described proposed mechanism and
to understand whether this reaction proceeds via a metal-
ligand cooperative mechanism,34 we performed the hydro-
genation of indole 1a using N-Me-substituted Mn-1 catalyst
(Scheme 5). As expected, no formation of indoline was
observed under the applied reaction conditions, indicating the
crucial role of species B for the catalytic cycle.
Scheme 5. Mechanistic Studies
a
Reaction conditions: 2 or 4 (0.25 mmol), Mn-1 (1−10 mol %) and
KOtBu (2.5-25 mol %) in toluene (1 mL) at 120−160 °C for 24 h.
Isolated yields are provided.
dehydrogenated using only 1 mol % of the catalyst at
120 °C for 24 h leading to 89% of indole. The liberated
hydrogen gas was detected using GC. Although the hydrogen
storage capacity for indoline is relatively low, 1.7 wt %
compared to the current favorite, the N-ethylcarbazole/
dodecahydro-N-ethylcarbazole system with a capacity to
store 5.8 wt % of hydrogen, its conversion to indole requires
low catalyst loading and comparable low temperatures, which
makes our developed catalyst system potentially interesting for
the LOHC concept. A higher catalyst loading (5 mol %) and
temperature (150 °C) were required for the successful
dehydrogenation of 3-methylindoline leading to product 1j
in 92% isolated yield. Harsher conditions had to be applied for
the dehydrogenation of 1,2,3,4-tetrahydroquinoxaline as well
as substituted 1,2,3,4-tetrahydroquinoxalines. Thus, by using 5
mol % of the catalyst and conducting the reaction at 160 °C for
24 h we could achieve 95% of quinoxaline. Substituted 1,2,3,4-
tetrahydroquinoxalines underwent dehydrogenation by using
10 mol % of the catalyst at 160 °C for 24 h.
In conclusion, we describe for the first time that a single
manganese catalyst can catalyze both the hydrogenation and
acceptorless dehydrogenation of N-containing heterocycles.
The products of both hydrogenation and dehydrogenation
reactions can be isolated in good to excellent yields and high
chemoselectivity. The applied catalyst Mn-1 is air and moisture
stable and can be synthesized using a readily available
manganese precursor and PhPNP-pincer ligand, highlighting
the practicability of the developed protocol. Mechanistic
studies indicate a metal−ligand cooperative catalysis.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01273.
Experimental data (PDF)
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For cobalt-catalyzed hydrogenation of heterocycles, see:. (b) Adam,
R.; Cabrero-Antonino, J. R.; Spannenberg, A.; Junge, K.; Jackstell, R.;
Beller, M. A General and Highly Selective Cobalt-Catalyzed
Hydrogenation of N-Heteroarenes under Mild Reaction Conditions.
Angew. Chem., Int. Ed. 2017, 56, 3216.
AUTHOR INFORMATION
Corresponding Author
■
Magnus Rueping − Institute of Organic Chemistry, RWTH
Aachen University, 52074 Aachen, Germany; KAUST Catalysis
Center (KCC), KAUST, Thuwal 23955-6900, Saudi Arabia;
orcid.org/0000-0003-4580-5227;
Email: magnus.rueping@kaust.edu.sa, magnus.rueping@
rwth-aachen.de
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Authors
Viktoriia Zubar − Institute of Organic Chemistry, RWTH
Aachen University, 52074 Aachen, Germany; KAUST Catalysis
Center (KCC), KAUST, Thuwal 23955-6900, Saudi Arabia
Jannik C. Borghs − Institute of Organic Chemistry, RWTH
Aachen University, 52074 Aachen, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01273
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was financially supported by the King Abdullah
University of Science and Technology (KAUST), Saudi
Arabia, Office of Sponsored Research (FCC/1/1974).
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