Aerobic iron-catalyzed site-selective C(sp3)–C(sp3) bond cleavage in N-heterocycles

Article abstract of DOI:10.1016/j.catcom.2021.106333

The kinetic and thermodynamic stability of C(sp³)–C(sp³) bonds makes the site-selective activation of these motifs a real synthetic challenge. In view of this, herein a site-selective method of C(sp³)–C(sp³) bon

Full text of DOI:10.1016/j.catcom.2021.106333

Catalysis Communications 157 (2021) 106333
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short communication
3
3
Aerobic iron-catalyzed site-selective C(sp )–C(sp ) bond cleavage in
N-heterocycles
*
David K. Leonard, Wu Li, Nils Rockstroh, Kathrin Junge, Matthias Beller
Leibniz-Institut für Katalyse e.V., Albert-Einstein-Straße 29a, 18059 Rostock, Germany
A R T I C L E I N F O
A B S T R A C T
The kinetic and thermodynamic stability of C(sp )–C(sp ) bonds makes the site-selective activation of these
motifs a real synthetic challenge. In view of this, herein a site-selective method of C(sp )–C(sp ) bond scission of
amines, specifically morpholine and piperazine derivatives, using a cheap iron catalyst and air as a sustainable
oxidant is reported. Furthermore, a statistical design of experiments (DoE) is used to evaluate multiple reaction
parameters thereby allowing for the rapid development of a catalytic process.
3
3
Keywords:
Iron
3
3
Oxidation
C–C bond activation
Design of experiments
3
3
1
. Introduction
1.1. C(sp )–C(sp ) bond activation
Iron is the most abundant metal in the universe, and due to its pro-
There is an ongoing surge in new methodologies for the activation of
3
3
pensity towards oxidation it is found in the earth’s crust as one of its
several ores, namely hematite (Fe ), magnetite (Fe ), and siderite
FeCO ). In the field of catalysis, no base metal has impacted the world
C(sp )–C(sp ) bonds which are ubiquitous within the framework of
organic compounds [12–17]. Due to their kinetic and thermodynamic
stability, traditional methods—such as the Criegee [18] and Malaprade
[19] reactions—are ill-suited transformations for organic compounds
bearing sensitive functional motifs. For this reason there has been an aim
towards realizing mild reaction conditions and greater functional group
tolerance. With this goal in mind, our group was able to establish a
2
O
3
3 4
O
(
3
quite like iron; in fact, heterogeneous iron catalysis has triumphed in
some of the world’s most important industrial processes [1]. For
instance, the Fischerꢀ Tropsch process has established itself as an
indispensable technology for the synthesis of liquid hydrocarbons and
has been implemented by leading petrochemical companies. Undoubt-
edly, the Haberꢀ Bosch process has had the most significant impact since
its introduction in 1913 at BASF. At present this remains the leading
industrial method for artificial nitrogen fixation, producing ammonia
3
3
copper-mediated system for the cleavage of C(sp )–C(sp ) bonds in
amines [20]. Following this initial report, we developed an improved
bimetallic cobaltꢀ manganese system with activity and selectivity to-
wards the cleavage of morpholine derivatives [21]. Although we were
able to shift to more earth-abundant metals, we were intrigued to utilize
cheap and non-toxic iron for such transformations (Fig. 1).
2 2
from N and H , and is a vital technology for securing global food pro-
duction. Notably, both revolutionary processes utilize iron-based cata-
lysts [2–4].
The contemporary literature has often highlighted the talents of iron
for enabling an extensive range of organic transformations [5–7].
Thanks to its position in the center of the 3d block of the periodic table,
iron may be considered by chemists as either an early or late transition
metal, and due to its formal oxidation states, which range from ꢀ 2 to
1
.2. Experimental design
Compared to classic optimization strategies, statistical design of ex-
periments (DoE) has gained increasing reputation among industrial
chemists in recent years as an effective methodology for reaction opti-
mization and identification of critical reaction parameters [22,23]. More
specifically, this paradigm shift is a result of:
+
6, it has a vast potential for all kinds of redox transformations
[
1,8–11]. New applications for iron are eagerly sought after, especially
in the field of catalysis, thanks to its ready availability, low cost, and
typically low toxicity.
1
. the development of parallel reactors, high-throughput experimen-
tation (HTE) and flow reactor setups having been implemented
widely,
*
Corresponding author.
E-mail address: matthias.beller@catalysis.de (M. Beller).
https://doi.org/10.1016/j.catcom.2021.106333
Received 17 March 2021; Received in revised form 8 June 2021; Accepted 16 June 2021
Available online 18 June 2021
1
566-7367/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

D.K. Leonard et al.
Catalysis Communications 157 (2021) 106333
DoE was used for efficient optimization of the reaction by mapping of
chemical space, analyzing multiple variables simultaneously. Advanta-
geously, not only were we able to employ a very cheap, readily avail-
able, and “biocompatible” iron catalyst but also utilize air as the most
green and sustainable oxidant. Notably, oxidation reactions in aerated
solvents inherently possess significant safety concerns, which must be
addressed appropriately. Indeed, organic chemists in academia but also
the pharmaceutical industry in particular try to avoid such synthetic
steps [28]. Starting materials tend therefore to be acquired in at least the
correct (or higher) oxidation levels. This can certainly generate an
additional hurdle in route design, and thus new practical methodologies
are readily sought to address this [29]. On the other hand it’s true that
aerobic oxidations are applied in several large and medium scale in-
dustrial processes, which demonstrates the possibilities to perform such
transformations in a selective, safe, and environmentally benign manner
[
26,27]. In our case, safety concerns were in large part circumvented by
using (synthetic) air which uses diluted oxygen in inert nitrogen, as well
as oxidation resistant solvents.
Fig. 1. Selected recent methods of metal catalyzed oxidative C–C bond cleav-
age reactions [20,21], and this work: iron-catalyzed C–C bond cleavage.
2
. Experimental
2
3
. the shift away from quality by testing towards the adoption of quality
by design (QbD), with the concept of design space becoming more
widely known,
2
.1. General experimental details
Most substrates were obtained from commercial sources and used as
. the Green Chemistry Principles [24] having encouraged chemists to
reduce waste output from chemical reactions and increase efficiency
by reducing the amounts of solvents and reagents used in chemical
processes.
supplied; others were prepared as detailed below.
All metal catalysts were obtained from commercial sources and used
as supplied.
Unless otherwise mentioned, all catalytic oxidation reactions were
carried out in 2 mL glass vials, which were set in an alloy plate and
placed inside a 300 mL autoclave (Parr® Instrument Company).
All oxidation reactions were performed in a Parr® Instrument
Company autoclave.
Interestingly, DoE tools are not widely adopted in academia despite
their advantages. In contrast to univariate—i.e. linear, or one-factor-at-
a-time (OFAT)—analyses, multivariate approaches to experimental
design allow expansive areas of chemical space to be explored in an
efficient and expedient manner [25].
Deuterated solvents were ordered from Deutero GmbH. NMR spectra
were recorded using Bruker 300 Fourier, Bruker AV 300 and Bruker AV
Since many factors can influence the outcome of a chemical reaction
4
00 spectrometers. Chemical shifts are reported in ppm, relative to the
(
e.g. conversion, yield, selectivity, byproduct formation), DoE can be an
deuterated solvent. Coupling constants are expressed in Hertz (Hz). The
following abbreviations are used: s = singlet, d = doublet, t = triplet,
and m = multiplet. The residual solvent signals were used as references
invaluable addition to the synthetic chemist’s toolbox. Not only can DoE
cut down on the number of experimental runs used in optimization, but
it also allows significant factors—and interactions between factors—to
be identified; this is simply not feasible using a one-factor-at-a-time
approach. What’s more, DoE can streamline the process of locating
the global maximum response for a reaction (i.e. the conditions
furnishing the most desirable outcome) by investigating multiple di-
mensions simultaneously (as illustrated in Fig. 2).
1
13
for H and C NMR spectra (CDCl
DMSO‑d
3
: δH = 7.26 ppm, δC = 77.12 ppm;
6
: δH = 2.50 ppm, δC = 39.52 ppm). All measurements were
carried out at room temperature unless otherwise stated.
GC-FID analyses were carried out using an Agilent 7890B gas chro-
matograph fitted with an Agilent HP5 column (30 m × 0.25 mm I.D. x
0
.25 m).
μ
In an effort to expand upon our previous methodologies, and build-
ing more sustainable practices, we herein report a new catalytic system
Solvents were used directly without further purification. HPLC grade
MeCN was supplied by Fisher Chemical.
3
3
for the site-selective cleavage of C(sp )–C(sp ) bonds in (cyclic) amines.
Scanning transmission electron microscopy (STEM) was performed
with a probe aberration-corrected JEM-ARM200F (Jeol Ltd., CEOS
Corrector) at 200 kV. The microscope is further equipped with an
Enfinium ER (Gatan) electron energy loss spectrometer. For STEM im-
aging a High-Angle Annular Dark Field (HAADF) and an Annular Bright
Field (ABF) detector were applied, while EELS acquisition was done with
the Annular Dark Field (ADF) detector. The solid sample was dried in
advance of the electron microscopy measurements and then placed
without any further pretreatment on a holey carbon supported Cu-grid
(
mesh 300), which was then transferred to the microscope. EEL
spectra were background subtracted and deconvolved.
2
2
.2. General procedure for the synthesis of substrates
.2.1. General procedure A (GP-A)
Fig. 2. Comparison between a univariate OFAT study (two sequential studies,
first exploring T, then p) (left) and a multivariate full-factorial study (one study
exploring T and p at the same time) for a hypothetical reaction. Dark blue re-
gions indicate more desirable responses. (For interpretation of the references to
colour in this figure legend, the reader is referred to the web version of
this article.)
A mixture of aryl bromide (10 mmol), morpholines (20 mmol),
K
2
CO
3
(20 mmol), CuI (1.0 mmol) and L-proline (2.0 mmol) in 10 mL of
◦
DMSO was heated at 90 C and for 24 h. The cooled mixture was par-
titioned between water and ethyl acetate. The organic layer was sepa-
rated, and the aqueous layer was extracted with ethyl acetate. The
2

D.K. Leonard et al.
Catalysis Communications 157 (2021) 106333
combined organic layers were dried over Na
2
SO
4
, and concentrated in
Unlike our recently reported [Co–Mn]/air system, iron(III) chloride
was able to perform oxidative cleavage outwith the class of morpholines
(Table 1). The catalyst’s activity towards 1,4-diphenylpiperazine (2a)
under the pre-optimized conditions using (2,2,6,6-tetramethyl-piper-
idin-1-yl)oxyl (TEMPO)—a stable free radical reagent—was particularly
encouraging. It is noteworthy to point out that the presence of pyridine
ligands highly influenced the yield of 2b (Table 1); a documented effect
of N-ligands in oxidations [20,21,31,32]. However, a reproducible
positive effect was only observed in the presence of the parent ligand.
Pyridines both substituted with electron-donating as well as electron-
withdrawing substituents gave inferior results.
vacuo. The desired products were isolated by silica gel column chro-
matography (n-heptane/ethyl acetate mixtures) [34].
2
2
.3. General procedure for catalytic oxidations
.3.1. General procedure B (GP-B)
A 4 mL glass vial equipped with a magnetic stir bar was charged with
aryl morpholine (0.5 mmol) and FeCl
capped, and the septum was pierced with a small needle. HPLC grade
acetonitrile (2 mL) was added via a 2 mL syringe. Pyridine (80 L; 2.0
3
(8.1 mg; 10 mol%). The vial was
μ
equiv) was added via a glass microsyringe. The vial was then placed into
an aluminium heating block and then sealed inside an autoclave (Parr®
Instrument Company). The autoclave was then pressurized with air (30
In contrast to our previously reported systems for C–C single bond
cleavage, which showed high activity towards a variety of amines (in the
case of [Cu]) and functionalized morpholines (in the case of [Co–Mn]),
◦
bar). The reaction mixture was stirred for 24 h at 100 C. Next, the re-
3
with this new FeCl catalyst system, better performance was obtained
action was cooled to room temperature. A sample of the reaction
mixture was analyzed by GC-FID and TLC. The product was purified via
flash column chromatography (RediSep® Rf + automatic column) using
heptane/ethyl acetate. Solvent was removed in vacuo to yield the
desired product.
with piperazine substrates. Notably, the [Co–Mn] system was found to
be completely ineffective with such substrates.
With a suitable catalyst, solvent and additives in hand for site-
3
3
selective C(sp )–C(sp ) bond cleavage in 2a to 2b, we postulated that
a DoE methodology is a suitable tool for establishing a more realistic
process. It is expected that the reaction parameters: catalyst loading,
temperature, air pressure, pyridine loading, and TEMPO loading could
all significantly influence the reaction yield of 2b (Table 2).
2
.3.2. General procedure C (GP-C)
A 4 mL glass vial equipped with a magnetic stir bar was charged with
,4-diphenylpiperazine (59.6 mg; 0.25 mmol), TEMPO (3.9–11.7 mg;
1
1
The rationale behind the ranges of the low-level (ꢀ ) and high-level
conditions (+) of the selected variables is that they must be large
enough to ensure any effects on reaction yield should be easily detect-
able. Additionally, using a wide range between these two values is one of
the best ways to improve the signal/noise ratio. A two-level half-frac-
tional (25 ) factorial design was selected to enable a large area of
chemical space to be covered whilst keeping the number of experimental
runs to a minimum and avoid compounding effects.
0–30 mol%) and FeCl (2.0–6.1 mg; 3–15 mol%) in that order. The vial
3
was capped, and the septum was pierced with a small needle. HPLC
grade acetonitrile (1 mL) was added via a 2 mL syringe. Pyridine
(
2.0–6.0 μL; 10–30 mol%) was added via a glass microsyringe. The vial
-1
was then placed into an aluminium heating block and then sealed inside
an autoclave (Parr® Instrument Company). The autoclave was then
pressurized with air (10–30 bar). The reaction mixture was stirred for
◦
2
4 h at 80–120 C. Next, the reaction was cooled to room temperature. A
Using a software statistics package (Minitab) [33], we generated a
list of all necessary experimental runs to cover the chosen design space.
Included in the design are four runs in the center of the design space (9
sample of the reaction mixture was analyzed by GC-FID and yield was
determined using n-hexadecane as an internal standard (see appendix
for GC-FID calibration graphs). Product isolation was achieved via flash
column chromatography (RediSep® Rf + automatic column) using a
suitable mixture of heptane/ethyl acetate determined by TLC. Solvent
was removed in vacuo to yield the desired product.
◦
mol% catalyst loading, 100 C, 20 bar air, 20 mol% pyridine, 20 mol%
TEMPO), leading to a total of twenty experimental runs. The yield of 2b
in each run was determined by gas chromatograph-flame ionization
detector (GC-FID) using n-hexadecane as an internal standard.
From first inspection of the data in Table 3, the most desirable results
are obtained using high temperature and high air pressure (entries 10,
3
. Results and discussion
To develop our expertise in the area of base metal-catalyzed C(sp )–C
1
1, 16). It was therefore unsurprising that mostly low yields were ach-
3
ieved at milder temperature and pressure (entries 3, 5, 9). This may be
3
3
3
(
sp ) bond cleavage reactions, we investigated various metal salts for the
explained by the high thermodynamic stability of C(sp )–C(sp ) bonds
thus making the reaction inaccessible without significant heating.
Notably, entries 4 and 6 reveal the possibility to achieve good product
yields under just 10 bar air pressure, thereby benefitting both conve-
nience and safety. The analysis of variance (ANOVA) table (Table S11)
was consistent with the observation that temperature and pressure were
favorable towards the yield of 2b. In fact, the ANOVA identified three
factors as being statistically significant in the reaction (i.e. p-values
<0.05 under the null hypothesis), these being: catalyst loading, tem-
perature, and pressure. In other words, the high-level conditions for
these three factors generated the best results. Whilst the presence of
TEMPO and pyridine had proven to be beneficial in the reaction, vari-
ation from 10 to 30 mol% had no statistically significant impact on the
yield of 2b.
cleavage of N-phenylmorpholine 1a under aerobic conditions [20,21].
In addition to our recently published [Cu]/air and [Co–Mn]/air systems,
several iron catalysts showed promising activity for this transformation
(
Table S3).
The most favorable results were obtained using iron(III) chloride
entry 7), although lower yields could also be obtained using iron(III)
(
nitrate nonahydrate (entry 5) and iron(II) phthalocyanine (entry 6).
Encouraged by these initial findings we opted to compare the perfor-
mance of the catalyst in various solvents (see Table S4) and found that
acetonitrile proved to be the most effective solvent, which is consistent
with our previously disclosed catalytic systems [20,21]. At this point it is
important to note that the use of organic solvents in oxidation reactions
is always potentially hazardous; especially performing reactions under
aerobic conditions without appropriate safety measures. Hence, we
completed all experiments in standard autoclave equipment with syn-
Based on the results vide supra, the decision was made to try to
explore higher temperatures and pressures, as well as greater amounts of
TEMPO and pyridine in solution. In all cases, catalyst loading was
maintained at 10 mol% (see Tables S12 & S13). Notably, the harsher
conditions employed were in fact disadvantageous and could not reach
the yield of 60% of 2b obtained in the first DoE screen.
thetic air as the oxidant—which contains just 20.5 ± 0.5% O
2
diluted in
N
2
gas—as an operationally safer system to pure O . In addition, we used
2
solvents with high resistance to autooxidation. Notably, the chosen
◦
solvent, acetonitrile, has an autoignition temperature of 524 C, as well
as lower and upper explosive limits of 4.4 and 16%, respectively (see
safety data sheets) [30], which allows for safe and reproducible work
under our reaction conditions. It should be also mentioned that in all
experiments we never observed any evidence of solvent oxidation.
Using the optimization process outlined above allowed us to isolate
derivatized morpholines and derivatized diphenylpiperazine in good
yields (up to 70%), as shown in Table 4. It is noteworthy to highlight that
such reactivity could not be realized with our previously reported
3

D.K. Leonard et al.
Table 1
Catalysis Communications 157 (2021) 106333
Influence of Pyridine Ligands on the Benchmark Reaction.
a
◦
Reaction conditions: 2a (0.25 mmol), FeCl
3
(10 mol%), TEMPO (20 mol%), ligand (20 mol%) in MeCN (2 mL), 20 bar air, 100 C. Yields
determined by GC-FID using n-hexadecane as an internal standard.
Table 2
Reaction Conditions Selected for DoE Analysis of Oxidative Cleavage of 2a Using
FeCl
Table 4
C–C Bond Cleavage Reactions
3
.
factor
low level (ꢀ )
high level (+)
catalyst loading (mol%)
3
15
◦
temperature ( C)
80
10
10
10
120
30
air pressure (bar)
pyridine loading (mol%)
TEMPO loading (mol%)
30
30
Table 3
a
Results of the Initial DoE Screen for Oxidative Cleavage of 2a .
b
entry
catalyst
loading
TEMPO
(mol%)
pyridine
(mol%)
air
temperature
yield
(%)
◦
pressure
(bar)
( C)
(
mol%)
1
2
3
4
5
6
7
8
9
3
10
10
30
30
10
10
30
30
10
10
30
30
10
10
30
30
20
20
20
20
10
10
10
10
30
30
30
30
10
10
10
10
30
30
30
30
20
20
20
20
10
10
10
10
10
10
10
10
30
30
30
30
30
30
30
30
20
20
20
20
120
80
25
38
5
15
3
80
15
3
120
80
45
7
15
3
120
120
80
52
30
33
12
59
56
52
41
36
16
60
15
3
80
a
Reaction conditions: a (0.5 mmol), FeCl
3
(10 mol%), pyridine (2.0 equiv) in
10
11
12
13
14
15
16
17
18
19
20
15
3
120
120
80
◦
MeCN (2 mL), 30 bar air, 100 C, isolated yield.
15
3
120
80
furnishing a 9% yield of 2b after reaction overnight (see Supporting
Information).
15
3
80
15
9
120
100
100
100
100
Scanning transmission electron microscopy (STEM) together with
electron energy loss spectroscopy (EELS) was performed to reveal the
nature of this precipitate (Figs. 3 & S1). The iron oxide particles are
found on a bulk phase which was proved to consist mainly of carbon, but
also contains some nitrogen and tiny amounts of iron.
c
51
c
9
44
c
9
40
c
9
45
a
Reaction conditions: 2a (0.25 mmol), FeCl
3
(3–15 mol%), TEMPO (10–30
b
mol%), pyridine (10–30 mol%) in MeCN (2 mL), 10–30 bar air, 80–120 ◦C.
Yields determined by GC-FID using n-hexadecane as an internal standard.
Center point conditions.
4
. Conclusions
c
In conclusion, a convenient iron-based catalyst is shown to be
3
3
effective for the site-selective cleavage of C(sp )–C(sp ) bonds in
diphenylpiperazine and derivatized morpholines. The activation of un-
catalytic systems.
The high activity of this benign system is further illustrated by the
lack of any noticeable induction period, leading to rapid conversion of
starting material and a 13% yield of 2b after just 30 min of reaction time.
Furthermore, after 8 h full conversion is observed for the model reaction
and the desired product is obtained in up to 60% yield, with no
detectable co-product formation.
3
2
strained and highly inert sp -hybridized centers to sp -hybridized
aldehyde motifs unlocks the potential for new functionalization of such
molecules. The use of air in this reaction is ideal as an oxidant. To the
best of our knowledge, this is the first example of a competent iron-based
3
3
catalytic system for the cleavage of C(sp )–C(sp ) bonds in unstrained N-
compounds. DoE provided a rapid and effective analysis of a complex C
During the benchmark reaction, the formation of a brown solid was
observed which proved to be somewhat catalytically active, capable of
3
3
(
sp )–C(sp ) bond cleaving reaction involving five variables. Three
4

D.K. Leonard et al.
Catalysis Communications 157 (2021) 106333
[
[
[
[
[
4] T. Rayment, R. Schl o¨ gl, J.M. Thomas, G. Ertl, Structure of the ammonia synthesis
catalyst, Nature 315 (1985) 311–313.
5] I. Bauer, H.J. Kn o¨ lker, Iron catalysis in organic synthesis, Chem. Rev. 115 (2015)
3
170–3387.
6] T.B. Boit, A.S. Bulger, J.E. Dander, N.K. Garg, Activation of C–O and C–N bonds
using non-precious-metal catalysis, ACS Catal. 10 (2020) 12109–12126.
7] A. Guðmundsson, J.-E. B ¨a ckvall, On the use of iron in organic chemistry,
Molecules. 25 (2020) 1349.
8] Y. Lee, N.P. Mankad, J.C. Peters, Triggering N
of coordinated NH and N silylation at trigonal bipyramidal iron, Nat. Chem. 2
2010) 558–565.
2
uptake via redox-induced expulsion
3
2
(
[
9] P. Hu, M. Tan, L. Cheng, H. Zhao, R. Feng, W.-J. Gu, W. Han, Bio-inspired iron-
catalyzed oxidation of alkylarenes enables late-stage oxidation of complex
methylarenes to arylaldehydes, Nat. Commun. 10 (2019) 2425.
[
10] G. Jin, G.W. Werncke, Y. Escudi ´e , S. Sabo-Etienne, S. Bontemps, Iron-catalyzed
reduction of CO
into methylene: formation of C–N, C–O, and C–C bonds, J. Am.
Chem. Soc. 137 (2015) 9563–9566.
2
Fig. 3. STEM HAADF (left) and STEM ABF (right) images of the precipitate
formed during the reaction. A group of iron oxide particles (see the brighter
parts in the left image) can be seen on the bulky phase, which contains
mainly carbon.
[11] S. Budweg, Z. Wei, H. Jiao, K. Junge, M. Beller, Iron–PNP-pincer-catalyzed transfer
dehydrogenation of secondary alcohols, ChemSusChem 12 (2019) 2988–2993.
[
[
[
[
12] D.-S. Kim, W.-J. Park, C.-H. Jun, Metal–organic cooperative catalysis in C–H and
C–C bond activation, Chem. Rev. 117 (2017) 8977–9015.
13] L. Souillart, N. Cramer, Catalytic C–C bond activations via oxidative addition to
transition metals, Chem. Rev. 115 (2015) 9410–9464.
14] S.P. Morcillo, Radical-promoted Cꢀ C bond cleavage: a deconstructive approach for
selective functionalization, Angew. Chem. Int. Ed. 58 (2019) 14044–14054.
variables—temperature, air pressure and catalyst loading—were found
to be significant in this reaction (i.e. p-values <0.05 under the null hy-
pothesis). Whilst the catalyst proved more active in the presence of
TEMPO and pyridine, the amount of these additives was not found to be
statistically significant (p-values >0.05) in the region of chemical space
explored in the factorial design.
3
15] X. Wen, X. Li, X. Luo, W. Wang, S. Song, N. Jiao, Intramolecular Csp –H/C–C bond
amination of alkyl azides for the selective synthesis of cyclic imines and tertiary
amines, Chem. Sci. 11 (2020) 4482–4487.
[
16] B. Wang, M.A. Perea, R. Sarpong, Transition metal-mediated C–C single bond
cleavage: making the cut in total synthesis, Angew. Chem. Int. Ed. 59 (2020)
18898–18919.
[
[
17] M. Murakami, N. Ishida, Cleavage of carbon–carbon
rings, Chem. Rev. 121 (2021) 264–299.
σ
-bonds of four-membered
Credit author statement
18] R. Criegee, Eine Oxydative Spaltung von Glykolen, Ber. Dtsch. Chem. Ges. B 64
(
1931) 260.
[
[
19] L. Malaprade, Bull. Soc. Chim. Fr. 3 (1934) 833.
David K. Leonard: Conceptualization, data curation, investigation,
writing - original draft, writing - review & editing. Wu Li: Conceptual-
ization, data curation, investigation, writing - review & editing. Nils
Rockstroh: Data curation, investigation, writing - original draft, writing
20] W. Li, W. Liu, D.K. Leonard, J. Rabeah, K. Junge, A. Brückner, M. Beller, Practical
3
3
catalytic cleavage of C(sp )ꢀ C(sp ) bonds in amines, Angew. Chem. Int. Ed. 58
(2019) 10693–10697.
[
21] D.K. Leonard, W. Li, K. Junge, M. Beller, Improved bimetallic cobalt–manganese
catalysts for selective oxidative cleavage of morpholine derivatives, ACS Catal. 9
-
review & editing. Kathrin Junge: Supervision, conceptualization,
(
2019) 11125–11129.
writing - review & editing. Matthias Beller: Supervision, conceptuali-
zation, writing - review & editing.
[22] S.A. Weissman, N.G. Anderson, Design of experiments (DoE) and process
optimization. A review of recent publications, Org. Process. Res. Dev. 19 (2015)
1
605–1633.
[
[
[
23] D. Lendrem, M. Owen, S. Godbert, DOE (Design of Experiments) in development
chemistry: potential obstacles, Org. Process. Res. Dev. 5 (2001) 324–327.
Declaration of Competing Interest
Authors declare that they have no competing interests.
Acknowledgments
24] P. Anastas, N. Eghbali, Green chemistry: principles and practice, Chem. Soc. Rev.
3
9 (2010) 301–312.
25] V.K. Aggarwal, A.C. Staubitz, M. Owen, Optimization of the Mizoroki–heck
reaction using Design of Experiments (DoE), Org. Process. Res. Dev. 10 (2006)
64–69.
[
26] R.A.F. Tom ´a s, J.C.M. Bordado, J.F.P. Gomes, p-Xylene oxidation to terphthalic
acid: a literature review oriented toward process optimization and development,
Chem. Rev. 113 (2013) 7421–7469.
We gratefully acknowledge the support from the Federal Ministry of
Education and Research (BMBF) and the State of Mecklenburg-Vor-
pommern. Financial support by Fonds der Chemischen Industrie
[27] J. Smidt, W. Hafner, R. Jira, J. Sedlmeier, R. Sieber, R. Rüttinger, H. Kojer,
Katalytische Umsetzungen von Olefinen an Platinmetall-Verbindungen Das
Consortium-Verfahren zur Herstellung von Acetaldehyd, Angew. Chem. 71 (1959)
(
Kekul ´e -Stipendium n. 103231) for D.K.L. is also acknowledged. We are
1
76–182.
grateful to Dr. Pavel Ryabchuk (Galapagos NV) for his valuable contri-
bution of ideas to the project. We thank the analytical staff of the Leibniz
Institute for Catalysis, Rostock, for their excellent service.
[28] A. Gavriilidis, A. Constantinou, K. Hellgardt, K.K. Hii, G.J. Hutchings, G.L. Brett,
S. Kuhn, S.P. Marsden, Aerobic oxidations in flow: opportunities for the fine
chemicals and pharmaceuticals industries, React. Chem. Eng. 1 (2016) 595–612.
[
29] P.M. Osterberg, J.K. Niemeier, C.J. Welch, J.M. Hawkins, J.R. Martinelli, T.
E. Johnson, T.W. Root, S.S. Stahl, Experimental limiting oxygen concentrations for
nine organic solvents at temperatures and pressures relevant to aerobic oxidations
in the pharmaceutical industry, Org. Process. Res. Dev. 10 (2014) 1537–1543.
30] (a) Sigma–Aldrich Acetonitrile Safety Data Sheet. https://www.sigmaaldrich.com
Appendix A. Supplementary data
[
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.catcom.2021.106333.
/
MSDS/MSDS/DisplayMSDSPage.do?country=GB&language=en&productNumber
=34851&brand=SIGALD&PageToGoToURL=https%3A%2F%2Fwww.sigmaaldr
ich.com%2Fcatalog%2Fproduct%2Fsigald%2F34851%3Flang%3Den (accessed
January 12, 2020);
References
(
b) INEOS Acetonitrile Safe Storage and Handling Guide.. https://www.ineos.co
m/globalassets/ineos-group/businesses/ineos-nitriles/she/2007_acetonitrile_bro
chure.pdf (accessed January 12, 2020).
[31] S.S. Stahl, Palladium-catalyzed oxidation of organic chemicals with O , Science
2
[
[
1] A. Fürstner, Iron catalysis in organic synthesis: a critical assessment of what it takes
to make this base metal a multitasking champion, ACS Cent. Sci. 2 (2016) 778–789.
2] E. de Smit, B.M. Weckhuysen, The renaissance of iron-based Fischer–Tropsch
synthesis: on the multifaceted catalyst deactivation behaviour, Chem. Soc. Rev. 37
309 (2005) 1824–1826.
[32] D. Wang, A.B. Weinstein, P.B. White, S.S. Stahl, Ligand-promoted palladium-
catalyzed aerobic oxidation reactions, Chem. Rev. 118 (2018) 2636–2679.
[33] Minitab 19. https://www.minitab.com (accessed December 14, 2020).
[34] D. Ma, Q. Cai, H. Zhang, Mild method for Ullmann coupling reaction of amines and
aryl halides, Org. Lett. 5 (2003) 2453–2455.
(
2008) 2758–2781.
3] M.M. Rodriguez, E. Bill, W.W. Brennessel, P.L. Holland, N
hydrogenation to ammonia by a molecular iron–potassium complex, Science 334
2011) 780–783.
[
2
reduction and
(
5