Manganese-Catalyzed Multicomponent Synthesis of Pyrroles through Acceptorless Dehydrogenation Hydrogen Autotransfer Catalysis: Experiment and Computation

Article abstract of DOI:10.1002/cssc.201802416

A new base metal catalyzed sustainable multicomponent synthesis of pyrroles from readily available substrates is reported. The developed protocol utilizes an air- and moisture-stable catalyst system and enables the replacement of themutagenic α-haloketones with readily abundant 1,2-diols. Moreover, the presented method is catalytic in base and the sole byproducts of this transformation are water and hydrogen gas. Experimental and computational mechanistic studies indicate that the reaction takes place through a combined acceptorless dehydrogenation hydrogen autotransfer methodology.

Full text of DOI:10.1002/cssc.201802416

Accepted Article
Title: Manganese Catalyzed Multicomponent Synthesis of Pyrroles via
Acceptorless Dehydrogenation Hydrogen Autotransfer Catalysis:
Experiment and Computation
Authors: Magnus Rueping
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10.1002/cssc.201802416
ChemSusChem
COMMUNICATION
Manganese Catalyzed Multicomponent Synthesis of Pyrroles via
Acceptorless Dehydrogenation Hydrogen Autotransfer Catalysis -
Experiment and Computation
Jannik C. Borghs,[a] Luis Miguel Azofra,[b] Tobias Biberger,[a] Oliver Linnenberg,[c] Luigi Cavallo,*[b]
Magnus Rueping*[a][b] and Osama El-Sepelgy*[a]
Abstract: A new base metal catalyzed sustainable multicomponent
synthesis of pyrroles from readily available substrates is reported.
The developed protocol utilizes an air and moisture stable catalyst
system and has been utilized to replace mutagenic α-haloketones by
readily abundant 1,2-diols. Moreover, the presented method is
catalytic in base and the sole by-products of this transformation are
water and hydrogen gas. Experimental and computational
mechanistic studies indicate that the reaction takes place via a
combined acceptorless dehydrogenation hydrogen autotansfer
methodology.
formations, releasing water as the only by-product (Scheme
1A).[4] A related concept is the acceptorless dehydrogenation
(AD) which permits the conversion of alcohols to carbonyl
compounds by liberating hydrogen gas without the need for a
stoichiometric oxidant (Scheme 1B).[5]
Following the concept of HA, pyrroles can be synthetized from
unsaturated 1,4-diols and primary amines.[6] Furthermore,
catalytic systems have been developed for the synthesis of
pyrroles using the AD concept from 1,4-diols and primary
amines or secondary alcohols and amino alcohols.[7] Moreover,
Beller and co-workers have reported three-component synthesis
of pyrroles using [Ru3(CO)12]/Xantphos catalytic system. The
authors proposed that the reaction might proceed via the AD
concept.[8]
Multicomponent reactions are valuable sustainable processes
for the construction of complex molecules in one pot from three
or more substrates. This strategy merges several elementary
reaction steps, which lead to minimize the amount of waste, and
simplifies the workup and purification steps.[1]
Pyrroles represent prominent and important chemical motifs in
medicinal-, agro- and advanced material chemistry. Classical
synthetic routes suffer from drawbacks mainly due to the
generation of substantial amounts of waste produced during the
multi-step pre-functionalization of substrates or by-product
formation.[2] Accordingly, there is a continuous need to develop
new catalytic systems which allow the direct and atom-economic
conversion of renewable and readily available substrates to
pyrroles.
Alcohols can be obtained from renewable biomass resources
and present promising sustainable feedstock chemicals. The
utilization of alcohols as substrates in the synthesis of fine
chemicals will hence contribute not only to the reduction of toxic
chemical waste but also to decrease CO2 emissions by avoiding
the use of carbon fossil sources.[3] One of the key concepts for
alcohol functionalization is hydrogen autotransfer (HA), which
has become a powerful tool for utilizing abundant alcohols as
building blocks for environmentally benign C-C and C-N bond
[a]
J. C. Borghs, T. Biberger, Prof. Dr. M. Rueping and Dr. O. El-Sepelgy
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: magnus.rueping@rwth-aachen.de
E-mail: Osama.Elsepelgy@rwth-aachen.de
Dr. L. M. Azofra, Prof. Dr. M. Rueping, Prof. Dr. L. Cavallo
KAUST Catalysis Center (KCC)
King Abdullah University of Science and Technology (KAUST)
Thuwal 23955-6900 (Saudi Arabia)
E-mail: Luigi.Cavallo@kaust.edu.sa
O. Linnenberg
[b]
[c]
Scheme 1. Acceptorless Dehydrogenation (AD) and Hydrogen Autotransfer
(HA) Catalysis.
Institute of Inorganic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
The replacement of noble metal catalyst by first row transition
metal catalysts is highly desirable due to ecological and
economic benefits and may also lead to the discovery of new
chemical reactivity.[9] Manganese is the third most abundant
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cssc.201802416
ChemSusChem
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transition metal in the earth crust and is recognized as a
sustainable alternative for toxic noble metal catalysts.[10-12] In our
continuous effort to develop new sustainable transformations
enabled by metal-ligand catalysts[13,14], we now report an
unprecedented manganese catalyzed construction of pyrroles
starting from readily available substrates: 1,2-diols, ketones and
primary amines (Scheme 1C). Notably, our experimental and
computational mechanistic studies on this multicomponent
reaction suggest that the reaction proceeds via a unified
acceptorless dehydrogenation hydrogen autotransfer strategy.
To the best of our knowledge, this is the first study that prove the
involvement of both processes of AD and HA in heterocyclic
synthesis.[15] In fact, we found that this strategy is crucial for the
successful activation of the vicinal 1,2-diols, providing a greener
alternative for the mutagenic α-haloketones.[16]
metal and the pincer ligand. (Table 1, entries 2, 3). Next, we
further optimized other reaction parameters. Our investigation
identified polar protic solvents to be most effective for the
desired transformation (Table 1, entries 1, 8-10), whereas
unpolar solvents were detrimental to the reaction (entries 4-7)
Screening of various bases confirmed that inexpensive KOtBu is
best for this transformation (entries 8-10). Further experiments
revealed that increasing the concentration to 1.0 M offers an
increased yield of 86% (entry 11).
Having established optimal conditions for the heterocyclization,
we moved on to demonstrate the applicability of our catalytic
system. An array of aryl and alkyl ketones in combination with 2-
phenylethylamine (2a) and ethylene glycol (3a) as model
substrates (Scheme 2A) could be transformed into the
corresponding pyrroles. Initially we were interested in using
various less active and challenging non-benzylic ketones.
Pleasingly, all the shown examples bearing different substituents
were isolated in high yields 4a–4h. Noteworthy, abundant alkyl
ketones were also successfully converted to the corresponding
bicyclic products 4g and 4h in very good yields. When we turned
our attention to the use of benzylic ketones we obtained the
respective pyrroles 4i-4m. To prove the scalability, we
conducted a gram scale synthesis of the pyrrole 4k’ and the
desired product was isolated in 78% yield. Regarding its
importance in medicinal chemistry[17] we also targeted
heteroatom substituted pyrroles by applying the respective α-
functionalized ketones. In fact, an α-alkoxy ketone showed high
reactivity and could be transformed into the product 4n in good
yield. Importantly, the benzamide containing pyrrole 4o was
obtained in excellent yield (94%). Next, various amines were
tested in combination with different ketones while keeping
We commenced our experimental study by synthesizing various
manganese pincer complexes and identified Mn-1 to be most
effective for the desired transformation. The new PNPPh-based
complex is bench stable and thus enables an operationally
simple, glovebox-free reaction set up. Suitable crystals of Mn-1
could be grown and were characterized by X-ray diffraction
(Table 1 top).
Table 1. Optimization of the Reaction Conditions.[a]
ethylene glycol as
a coupling partner (Scheme 2B). All
corresponding pyrroles were obtained in moderate to excellent
yields. Specifically, different ketones in combination with n-
hexylamine afforded products in good yields 5a-5f. It was further
demonstrated that different amines such as benzylamine or
cyclohexylamine were also suitable for this cascade
transformation 5g-5i. Despite its weak nucleophilicity, toluidine
showed significant reactivity and could be transformed into N-
aryl substituted pyrrole 5j in moderate yield. Gratifyingly, even
the sterically demanding 1-adamantylamine could be converted
to the respective pyrrole 5k. To our delight, an amino alcohol
was selectively converted to the pyrrole 5l.
In order to provide highly substituted pyrroles, we employed an
array of different vicinal diols giving the corresponding pyrroles
in high yields (Scheme 2C). Interestingly, symmetrical
disubstituted aromatic, aliphatic as well as cyclic diols could be
used for this transformation giving good yields of the
corresponding fully-substituted pyrroles 6a-6c and tetra-
substituted pyrrole 6d. If mono-substituted unsymmetrical diols
were employed, two regioisomers can be formed. However, in
entry
catalyst
solvent
base
yield [%]
1
2
Mn-1
Mn(CO)5Br
-
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
toluene
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOH
65
<5
<5
20
28
16
16
43
23
41
86
70
3
4
Mn-1
Mn-1
Mn-1
Mn-1
Mn-1
Mn-1
Mn-1
Mn-1
Mn-1
5
1,4-dioxane
Me-THF
6
7
CPME
8
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
neat
9
K2CO3
Cs2CO3
KOtBu
KOtBu
10
11[b]
12
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), 3a (1.5 mmol), [Mn]
catalyst (2 mol %) in t-amyl alcohol (0.5 M), 135 °C, 24 h under argon
atmosphere. Yield determined by GC using mesitylene as an internal standard.
[b] 1.0 M reaction mixture. CPME = cyclopentyl methyl ether.
For our model reaction system, we investigated the formation of
the substituted pyrrole 4a by using propiophenone )1a(,
2-phenylethylamine (2a) and ethylene glycol (3a). Thus, a
solution containing substrates in dried solvent, Mn-complex and
20 mol% of a base was heated to 135 °C for 24 h. To our delight,
by applying Mn-1, promising catalytic activity was observed and
the desired pyrrole was obtained in 65% yield (Table 1, entry 1).
Control experiments demonstrated the crucial role of both, the
all cases either
a
single regioisomer or
a very high
regioselectivity (95:5) was obtained with substitution occurring in
R4 in pyrroles 6e-6h. It is important to note that when the 1-(2-
methoxyphenyl)propan-2-one was used as
a
ketone in
combination with ethylene glycol, the C-H alkylation usually
takes place at the benzylic carbon (Scheme 2A, example 4m).
To our surprise, using the same ketone in combination with
phenyl or diphenyl substituted diols, the alkylation reaction
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10.1002/cssc.201802416
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occurs on the free methyl group affording a different regioisomer
(Scheme 2C, examples 6d and 6h). This observation led to the
synthesis of new highly substituted pyrroles which are difficult to
prepare by means of other methods.
Afterwards we decided to conduct experiments to prove the role
of the metal-ligand catalyst. When we performed the reaction
shown in Scheme 3 without catalyst and replacing the 1,2-diol
by an α-hydroxy ketone, only trace amounts of the pyrrole 6a
were observed. However, when 2,3-butandiol and Mn-1 were
used, 6a was obtained in 43% yield (Scheme 3). Furthermore,
we have analyzed the reaction atmosphere of the model
reaction using gas chromatography (Table 1, entry 11) and
detected the presence of hydrogen gas. These experimental
results indicate that the metal-ligand complex not only catalyzes
the AD process but also the HA process.
Scheme 3. Experimental Mechanistic Investigations
We subsequently carried out a detailed DFT study and selected
the multicomponent reaction between glyceraldehyde,
propiophenone and n-hexylamine catalyzed by Mn-1 as the
model reaction.[18,19] Initially, the uncatalyzed reaction between
the primary amine and the ketone leads to the formation of an
imine which is in equilibrium with the corresponding enamine.
The latter may undergo a C-H or N-H addition reaction with the
in situ generated glycolaldehyde or glyoxal. This establishes the
existence of four plausible reaction pathways (see Fig. S3). The
DFT calculations, the experimental investigations and the
observed selectivity (Scheme 2, examples 6e - 6h) suggest that
the reaction most likely occurs through the C-H alkylation of
enamine with in situ generated glyoxal (See SI for details).
Figure 1 illustrates that the Mn complex acts as a catalyst for
acceptorless dehydrogenation hydrogen autotransfer processes.
The first catalytic cycle involves AD of ethylene glycol to
glycolaldehyde and hydrogen gas (Figure 1A). The second
catalytic cycle involves a crucial HA process consisting of metal
catalyzed activation of glycoladehyde by shuttling a hydrogen
molecule required for the hydrogenation of the azadiene
intermediate (Figure 1B). Specifically, the ethylene glycol
dehydrogenation (AD cycle) starts with one of the -OH groups of
ethylene glycol interacting with the [Mn] species A to give
complex B, with a slightly endergonic binding Gibbs free energy
of 4.0 kcal mol-1 at 135 °C and using 1-butanol as solvent. This
complex is characterized by the presence of two interactions, in
which Mn acts as electrophilic center via a Mn···O interaction,
while the sp2 carbon in one of the arms of the non-innocent PNP
ligand acts as nucleophilic center through a C···H interaction
with the H atom of the ethylene glycol OH group. Proton transfer
from the alcohol occurs via transition state B-C with a free
energy barrier of 10.3 kcal mol–1 from A, and leads to
intermediate
C
laying -2.2 kcal mol–1 below A. This
aromatization-dearomatization process has been thoroughly
studied in metal-PNP and PNN complexes as an important
process providing the lowest energy pathways.[20]
Scheme 2. Scope of the Manganese Catalyzed Acceptorless
Dehydrogenation Hydrogen Autotransfer.
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10.1002/cssc.201802416
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Figure 1. Proposed reaction mechanism of the heterocyclization via a unified acceptorless dehydrogenation hydrogen autotransfer concept catalyzed by Mn-1.
Calculated Gibbs free reaction and activation energies at 135 °C, are shown in kcal mol–1 at the M06/TZVP//PBE/SVP(H,C,N,O,P)-TZVP(Mn) computational level
using 1-butanol as solvent. Note: P and R groups refer to PPh2 and n-hexyl, respectively.
.
The following hydride transfer occurs via the formation of
complex D, which represents the highest energy intermediate of
the dehydrogenation cycle, 15.3 kcal mol–1 relative to A. The
hydride transfer occurs through transition state D-E. This is
assumed to be an almost barrier-free process, as transition state
D-E is only 1.1 kcal mol–1 above intermediate D when electronic
energies in solution at the PBE/SVP(H,C,N,O,P)-TZVP(Mn) level
of theory are considered (i.e., the computational protocol used to
locate geometries). The resulting [Mn]-H2···glycolaldehyde
complex E is located 0.7 kcal mol–1 above A. The following
release of glycolaldehyde is exergonic by 8.5 kcal mol–1 and
leads to F. The acceptorless dehydrogenation cycle closes with
the regeneration of the catalyst by H2 release, in a process
presenting a kinetics penalty of 30.5 kcal mol–1 relative to F.
We have also carried out calculations for the case in which
proton and hydride transfers from glyceraldehyde to the Mn(I)-
PNP catalytic species occurs via a concerted pathway. The
corresponding activation Gibbs free energy is 3.4 and 2.3 kcal
mol–1 less stable than those computed for transition states B-C
and D-E, respectively. In this line, the proposal of a step-wise
mechanism in which hydride transfer might occur before the
proton transfer during AD cycle indicates disfavored kinetics,
with an activation barrier of 59.8 kcal mol–1 relative to A.
Subsequently the HA cycle has been investigated by DFT
analysis (Figure 1B). The first part of the HA process involves
the dehydrogenation of glycoaldehyde to glyoxal by the
hydrogen transfer to the Mn- and N-centers that also result in
the hydrogenated catalytic species, F´. In this process, proton
transfer exhibits a Gibbs free activation energy of 8.0 kcal mol–1,
G-H, while hydride transfer is carried out via the formation of
complex I, 11.7 kcal mol–1, also through a barrier-less process.
The second part of the HA process involves the endergonic
interaction between the manganese species F´ bearing shuttled
hydrogen molecule with the azadiene intermediate that has
resulted from a C-H alkylation reaction. This intermediate is
formed by the addition of glyoxal with the enamine compound, a
coupling that is exergonic by 8.2 kcal mol–1. In more detail,
hydride transfer from the Mn atom to the sp2 carbon atom
positioned β to the CHO group occurs via transition state K-L
and Gibbs free activation energy of 27.1 kcal mol–1 relative to F´.
The proton transfer occurs through transition state L-M and a
free energy barrier of 35.6 kcal mol–1 relative to L. This penalty
represents the highest kinetics impediment of the whole reaction
in which the Mn(I)-PNP catalytic species participates since
partial cyclization of the substrate is seen in L by NC(sp2)HO
bond formation. Finally, the released hydrogenated azadiene
can undergo cyclization to the observed pyrrole derivative with a
free energy gain of 29.1 kcal mol–1.
In conclusion, we have reported a new base metal catalyzed
heterocondensation cascade via acceptorless dehydrogenation
hydrogen autotransfer methodology. The reaction is catalyzed
by a new homogeneous base metal catalyst based on an
inexpensive and air stable manganese complex bearing a PNP
ligand. The great potential of our catalytic system was
demonstrated by the synthesis of more than 35 different
substituted pyrroles in good yields using renewable substrates
and only catalytic amounts of base. Importantly, water and
hydrogen gas are the sole by-products. Computational studies
support an acceptorless dehydrogenation hydrogen autotransfer
reaction mechanism in which the metal-ligand complex plays a
dual role for the acceptorless dehydrogenation of ethylene glycol
followed by non-typical hydrogen autotransfer process.
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Acknowledgements
J.C.B. is thankful for financial support of the German Federal
Environmental Foundation (DBU). L.M.A. and L.C. acknowledge
King Abdullah University of Science and Technology (KAUST)
for support. We thank KAUST Supercomputing Laboratory for
using the supercomputer Shaheen II and providing the
computational resources.
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Keywords:
Acceptorless
Dehydrogenation,
Hydrogen
Autotransfer, Base Metals, Alcohols, Heterocycles
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with the SVP basis set for main group atoms and the TZVP basis set
for Mn. Single-point energy refinement calculations were done at
M06/TZVP level. Solvent effects (1-butanol) were included via the PCM
model at both steps. All calculations have been performed through the
facilities provided by the Gaussian09 package. See the Supporting
Information for full computational details.
[8]
[9]
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.
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10.1002/cssc.201802416
ChemSusChem
COMMUNICATION
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COMMUNICATION
Jannik C. Borghs,Luis Miguel
Azofra,Tobias Biberger, Oliver
Linnenberg, Luigi Cavallo,* Magnus
Rueping,* Osama El-Sepelgy*
Page No. – Page No.
Title Multicomponent Synthesis of
Pyrroles via Acceptorless
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Dehydrogenation Hydrogen Autotransfer
Manganese Catalysis - Experiment and
Computation
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