Environmentally Friendly Synthesis of Indoline Derivatives using Flow-Chemistry Techniques

Article abstract of DOI:10.1002/ejoc.201700849

Flow chemistry proved to be a valuable technique to improve the synthesis route to melanin-concentrating hormone receptor 1 (MCHr1) antagonists with the 1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole scaffold. A one-step route for the heterogeneous catalytic hydrogenation of ethyl 4-(2-nitrophenyl)-3-oxobutanoate for the synthesis of ethyl 2-(2,3-dihydro-1H-indol-2-yl)acetate was developed, and the use of common reducing chemicals was avoided. N-Alkylation of the indoline nitrogen atom was also optimized by using a purpose-built flow reactor and by design of experiment (DoE). Applying an optimal set of parameters allowed us to decrease the amount of carcinogenic 1,2-dibromoethane used by a factor of 10. Additionally, nearly complete conversion was achieved in a fraction of the original reaction time (30 min vs. 4 d); therefore, the productivity (space-time yield) of the flow-reactor system was proven to be ca. 200 times higher than that of the batch process.

Full text of DOI:10.1002/ejoc.201700849

A Journal of
Accepted Article
Title: Environment-Friendly Synthesis of Indoline Derivates Using Flow
Chemistry Techniques
Authors: Róbert Örkényi, Gyula Beke, Eszter Riethmüller, Zoltán
Szakács, János Kóti, Ferenc Faigl, János Éles, and István
Greiner
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700849
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700849
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10.1002/ejoc.201700849
European Journal of Organic Chemistry
FULL PAPER
Environment-Friendly Synthesis of Indoline Derivatives Using
Flow Chemistry Techniques
Róbert Örkényi,*[a] Gyula Beke,[b] Eszter Riethmüller,[c] Zoltán Szakács,[b] János Kóti,[b] Ferenc Faigl,[a]
János Éles[b] and István Greiner[b]
numerous synthetic methods leading to these structures can be
Abstract
found in the literature, and the frequently applied methods have
been summarized in recent reviews.[10,11]
Flow chemistry proved to be a valuable technique to improve the
1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole
derivatives
of
discovery chemistry route to melanin-concentrating hormone
receptor (MCHr1) antagonists with 1H,2H,3H,4H,5H-
general formula 1 are melanin-concentrating hormone receptor 1
(MCHr1) antagonists for the treatment of obesity through
regulation of appetite.[12] Target molecules were first prepared
using the discovery chemistry route (Scheme 1.), which provided
material for in vitro and in vivo studies. During the preclinical
development phase, revision and optimisation of the original
synthetic route was inevitable to deliver the required quantity of
a selected derivative of 1.
1
[1,4]diazepino[1,7-a]indole scaffold.
Novel, one-step heterogeneous catalytic hydrogenation for the
synthesis of ethyl 2-(2,3-dihydro-1H-indol-2-yl) acetate was
developed from ethyl 4-(2-nitrophenyl)-3-oxobutanoate to avoid
commonly used reducing chemicals.
The N-alkylation reaction of the indoline nitrogen was also
optimised using a purpose-built flow reactor and
design of experiments. Applying the optimal set
of parameters allowed us to decrease almost
ten-fold the excess of carcinogenic 1,2-
dibromoethane. Additionally, nearly complete
conversion was achieved in a fraction of the
original reaction time (30 min vs. 4 days);
therefore, the productivity (space time yield) of
the flow reactor system is proved to be ca. 200
times more than the batch process.
Introduction
Many biologically active natural products contain
indole or the synthetically more challenging
indoline scaffolds. These compounds serve as
an
important
and
rich
source
of
pharmaceuticals.[1–3] Several 7-aryl azepinoindolines showed
selective 5-HT2C receptor activities,[4,5] polycyclic indoline
derivatives were tested as sensitizers of bacteria against
β-lactam antibacterial agents,[6] and other derivatives were
described as promising human protein kinase inhibitors.[7]
Recently, some novel indoline derivatives have also been
Scheme 1. The original batch-wise synthetic route for the synthesis of 1. The
highlighted suboptimal steps were optimised in flow. Reduction: see Table 1.;
EtOH: ethanol, AcOH: acetic acid, ACN: acetonitrile. The synthesis of 2 can be
found in Supporting Information (SI).
inhibitors[8],
and
In the introductory section we discuss the known synthetic
possibilities of the synthesis of the key intermediate (7) and its
precursors in a retrosynthetic fashion. Then, the original route
(Scheme 1.) will be analysed, and the investigation of the most
problematic, suboptimal steps under flow chemistry techniques
are described.
We found only one published process for the preparation of
diazepino-indole-one (7) by ring closing reaction of the
bromoethyl-indoline (5) that can be obtained in the nucleophilic
substitution of the corresponding 1H-indoline (4) with 1,2-
dibromoethane.[4,5,12]
Ethyl 2-(2,3-dihydro-1H-indole-2-yl) acetate (4) can be
synthesised in two main routes according to the literature. One
of them is the preparation from N-protected aminophenyl
derivatives containing ethyl but-2-enoates, from which the target
molecule (4) can be obtained by aza-Michael reaction.[13–15] The
other main possibility is the reduction of the corresponding
indole (3). According to the literature, 3 can be reduced by
sodium [cyano-trihydrido-borate(III)] (Na(CN)BH3) in acetic
described
as
apoptosis
protein
monoacylglycerol acyltransferase-2 inhibitors.[9] Accordingly,
[a]
R. Örkényi* and Prof. Dr. F. Faigl
Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics,
Budafoki út 8, H-1111 Budapest, Hungary
E-mail: orkenyi.robert@gmail.com
Homepage: https://www.linkedin.com/in/róbert-örkényi-38122490/
Dr. J. Éles, Dr. Gy. Beke, Dr. Z. Szakács, J. Kóti and Dr. I. Greiner
Gedeon Richter Plc.,
Gyömrői út 19-21., H-1103 Budapest, Hungary
Dr. E. Riethmüller
Department of Pharmacognosy,
[b]
[c]
Semmelweis University
Üllői út 26., H-1085 Budapest, Hungary
At the time of contribution she has worked at Gedeon Richter Plc.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700849
European Journal of Organic Chemistry
FULL PAPER
acid[4,5] or with borane trimethylamine complex (Me3N•BH3), in
highly acidic media (TFA).[16–18]
Considering the difficulty of the synthesis of ethyl but-2-enoates,
we chose the second pathway involving the indole 3.
The syntheses of ethyl 2-(1H-indol-2-yl) acetate (3) can also be
divided into two main groups, excluding those reactions, where
hydrogenation reaction that makes the one-step synthesis of 4
possible. We also investigated the N-alkylation reaction of 4 by
1,2-dibromoethane in order to decrease the reaction time, the
dilution, and the high excess of the carcinogenic reagent.
The application of flow chemistry techniques made this
optimisation procedure faster and safer, and allowed the
exploration of novel synthetic possibilities.
This paper is organized into two main sections as follows:
investigation of the reductive ring closing reaction of 2 together
with the reduction of 3 indole to 4 2,3-dihydroindole, and the
optimisation of the N-alkylation reaction of 4.
functional group addition[19,20]
,
conversion[21–23] and ring
contraction[24] reactions occurred or 3 was formed as a side-
product[25,26]. Several authors used 2-amino-benzylalcohol as
starting material, from which a Wittig-precursor could be
obtained
by
the
formation
of
corresponding
triphenylphosphonium salt followed by an N-acylation
reaction.[16,27–29] Indoline (3) can be obtained in good yield this
way; nevertheless, the used intramolecular Wittig-reaction’s low
atom efficiency is not ideal for large scale production.
Investigation of the continuous catalytic hydrogenation in
the heterogeneous continuous-flow hydrogenator
The other examples[5,30–34] involve reductive cyclization of 2, out
of which the heterogeneous catalytic reduction of the nitro group
followed by ring closure[30–32] seemed to be the most preferred
way for preparation 3.
Intermediate 2 can be obtained from 2-nitrophenylacetic acid (7)
starting material, which was used for acylation of malonic
ester[30,31,35,36] or ethyl acetoacetate[35,37–39] in the presence of
strong bases, then the resulting intermediates were transformed
into 2 with small to good yields. The most promising route
involves the preparation of 8 as an intermediate.[32–34] It can be
obtained from 9 acid chloride and deprotonated Meldrum’s acid
(10) under smooth conditions using diisopropylethylamine
(DIPEA) as a base. Heating of this intermediate (11) in ethanol
provides 2 in excellent yield.
In this article, we would like to highlight the numerous benefits
that flow chemistry[40–42] can add to the development of the
synthesis of lead compounds. One of them is the safe
implementation of the hazardous reactions,[43] because flow
technology prevents the direct contact of the chemists with the
toxic reagents. Heterogeneous continuous-flow hydrogenator
equipment, such as the H-CubeTM reactor, enables the work with
pyrophoric hydrogenation catalyst in a safe manner, without
hydrogen cylinder in the laboratory.[40,44–48] Moreover, using flow
chemistry for optimisation studies can significantly decrease the
required time. The CatCartTM system used in this reactor system
allows rapid catalyst screening, while working with small
amounts of intermediates makes the optimisation process more
efficient in an economic point of view as compared to batch-wise
reactions.
Next, we investigated the reductive cyclization reactions of 2 to
ethyl-(1H-indole-2-yl)-acetate (3) that have been described in
literature (shown in Table 1.).
Reduction with zinc in acidified reaction media (Table 1, entry 1)
was neglected because of the fact, that it uses huge excess of
heavy metal; and it cannot be scaled up due to stirring issues.
Titanium-trichloride worked well as a reductive agent (Table 1,
Entry 2), but this reaction requires large amounts of buffer
solution, which decreases its environmental friendliness.
Nevertheless, the palladium catalysed transfer hydrogenation
reaction (Table 1, Entry 3) gave the best yield, while the catalytic
hydrogenation reaction with hydrogen gas (Table 1, Entry 4)
also showed excellent yield, with the benefit of easier work up
procedure: there is no need to remove the excess of the
HCOONH4 reagent by extraction.
Table 1. Comparison of the known reductive cyclization reactions of 2 into 3.
Yield[a]
(%)
Yield[Lit.]
(%)
Entry
Reaction parameters
[b]
1
2
Zn (89 equiv.), sat. NH4Cl/H2O, THF, 2h, rt
-
95[34]
75[33]
TiCl3 (7 equiv.; 10%) in HCl/H2O (~10-
20%), NH4OAc/H2O (4M), acetone, 1 h, rt
75
96
91
3
4
10% Pd/C, HCOONH4 (11 equiv.), EtOH,
1 h, rt
88[30]
[c][32]
10% Pd/C, H2 (atm. pressure), EtOH, 20 h
-
[a] Isolated yields, for procedures see SI; [b] The literature method has not
been tested; [c] No yields were given. The reaction was carried out at 3.5 bar
H2 pressure, 96 hours. THF: tetrahydrofuran, rt: room temperature.
Results and Discussion
Heterogeneous catalytic hydrogenation reaction using
continuous-flow reactors are wide spread as a result of its
advantages.[45,48,49] In the beginning of our work, we screened
three different catalysts using the same conditions in the
heterogeneous continuous-flow hydrogenator (Scheme 2.), the
results are shown in Table 2.
Raney-nickel catalyst (Table 2, Entry 1) appeared to be less
active and selective than palladium catalysts. Both batch (Table
1, Entry 4) and flow results (Table 2, Entry 2) were consistent
with each other using charcoal supported palladium, good
conversion was reached, but selectivity values were not optimal.
Our aim was to develop an environmental-friendly, scalable, and
robust
synthesis
of
novel
3,9,11-trisubstituated-
1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole derivatives (1). To
achieve this, we used flow chemistry technology only in those
reactions, where it offered advantages as compared to batch
reactions. Systematic investigations were carried out in our
laboratory to find a continuous heterogeneous catalytic method
for nitro group reduction and cyclization of 2. In addition, we
wished to develop a novel consecutive heterogeneous catalytic
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Almost quantitative yield could be achieved with aluminium-
oxide supported palladium catalyst (Table 2, Entry 3), in which
case the reaction workup can be simplified to an evaporation.
polymerization caused by even weak electrophiles, since it is
known that
indoles
are highly activated
aromatic
compounds.[58,59] Unfortunately, over-hydrogenation remained an
issue in acidic media too resulting in the formation of significant
amount of by-products (mainly octahydro-indoles).[50]
During the optimisation, multiple parameters were considered
such as the solvent, the quality and the quantity of the acid
catalyst, and the temperature. Although, the closest state of art
of indole selective reduction was carried out at 30 bar hydrogen
pressure with platinum catalyst,[50] we have chosen the cheaper
palladium catalyst. We wished to achieve indole reduction at
atmospheric pressure, which is beneficial in the perspective of
the scale-up, since there is no need for autoclave operation to
perform the reaction. Consequently, all experiments were
carried out at atmospheric pressure (full H2 mode). The main
optimisation steps are shown in Scheme 3.
In this case, the previously applied water cannot be used as
solvent because in the acidic media, the ester function would be
hydrolysed. Out of three solvents employed (EtOH, EtOAc and
AcOH), acetic acid proved to be the best (Scheme 3, Entry 2). It
correlates with the previous findings[50] that the selectivity
towards 4 is increased with the increasing nucleophilicity of the
solvent. It means that less polymerized by-product is formed
along with less N-hydroxyl derivative[37] of 3. This is because the
more apolar the solvent is, the more nucleophile the aniline and
N-hydroxyl aniline compounds are. In the latter case the ring
closing reaction followed by the loss of water in the geminal di-
alcohol intermediate is faster than the hydrogenation (see SI:
Table S2). Since the reduction of N-hydroxyl indole derivative
requires more reaction time, or harsher conditions, using EtOAc
as solvent results in the main product with the 220 m/z is the
ethyl 2-(1-hydroxy-1H-indol-2-yl)acetate, which is the N-hydroxy
derivative of 3 indole (based on the literature[37] and the MS
spectra of the LC-DAD-MS).
Scheme 2. Heterogeneous continuous-flow reduction using H-CubeTM reactor.
Catalyst screen and optimisation of the consecutive hydrogenation for the
novel indoline synthesis.
Table 2. Results of the catalyst screening.[a]
Entry
Catalyst
Conversion
(%)[b]
Selectivity (3)
Selectivity (4)
(%)[b]
(%)[b]
1
2
3
Ra-Ni
65.6
33.0
91.4
98.5
0.0
0.7
0.1
Nevertheless, the acid catalyst screen (TFA: trifluoroacetic acid;
MsOH: methanesulfonic acid; TfOH: trifluoromethanesulfonic
acid) in the previously mentioned 3 solvents (see SI: Table S2)
showed that the combination of methanesulfonic acid in acetic
acid has provided the best results (Scheme 3, Entry 3), all other
selectivity towards 4 was less than 6% in the combinations of
these 3 solvents and 3 acid catalyst.
10% Pd/C
10% Pd/Al2O3
100.0
100.0
[a] All experiments were performed in the H-CubeTM device in 0.05 M ethanol
solution of 2, with flow rate of 0.5 mL min-1 at room temperature, using full H2
mode (atmospheric pressure of hydrogen); [b] Determined by LC-DAD-MS.
Next, we have tested the effect of quantity of the acid catalyst
(1-3-6 equivalent) along with the concentration (in the range of
0.005 M to 0.05 M; see SI: Table S3.) to the reaction. On the
one hand diluted solutions are not only favourable in flow
hydrogenation reactions to ensure that hydrogen excess is not
the limiting factor, but in this case it also decreases the
possibility of the polymerisation side reaction, that occurs the
protonated 3 (indolenium cation) reacts in an electrophilic
aromatic substitution with 3.
We have also observed the formation of small amount of the
over-reduced product (4) when charcoal supported palladium
was used; therefore, it seemed logical to develop a consecutive
catalytic hydrogenation method to produce compound 4 from 2
without the isolation of the indole (3).
Heterogeneous catalytic hydrogenation of N-unprotected indoles
can be challenging due to many difficulties, such as highly
resonance-stabilized aromatic core, which requires harsh
reaction conditions. Furthermore, these compounds and the
product as base are able to poison the catalyst metal. The most
promising results were achieved by Kulkarni et al.,[50] who used
acid catalyst to protonate indoles at C-3 position in order to
disrupt the aromaticity and generate an iminium ion, which can
be hydrogenated under less harsh conditions. Nevertheless,
using acid as a catalyst[37,51–57] raises further difficulties, such as
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10.1002/ejoc.201700849
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module® was used in the heterogeneous continuous flow
alkylation. Since no reaction occurs at room temperature, we
could simplify the flow system. There were no need for two
separate pumps and a mixer unit to combine the solution of
the substrate indoline (4) with the reagent 1,2-dibromoethane
(Scheme 4.).
The pre-mixed reaction solution was simply pumped through
the packed bed reactor filled with caesium carbonate. While
the conversion was almost complete, the selectivity towards
5 was fairly low (Table 3.). Based on the literature[60,61] data
and the MS spectra of the LC-DAD-MS measurements of the
crude reaction mixture, the main monobromo-compound with
the 355/357 m/z is assumed to contain the 2-bromoethyl
group with N-carbamate linker, which is presumably formed
upon the reaction of the 4 and CO2. Due to the fact that this
approach has not been successful, we have tried to use a
solid-phase supported basic reagent instead of the solid
inorganic base, which could not serve as a source of carbon-
dioxide. DMAP bound to silica (Silia-DMAP; SiliaBond®) was the
chosen base. In this case, both conversion and selectivity
depended on the residence time (Table 4, for details see SI.).
Scheme 3. Main steps of the optimisation of the heterogeneous continuous-
flow reduction using H-CubeTM reactor. All experiments were carried out at
atmospheric pressure.
The best result still had medium selectivity and low conversion in
the second step (Scheme 3, Entry 4), so we elevated the
reaction temperature to accelerate the reaction using the
same flow rate and residence time, which gave the
product (4) with good conversion and selectivity (Scheme
3; Entry 5).
The best reaction parameters were also used in a batch
reaction, in which 4 was obtained with 75% of isolated
yield. By this, we have developed a novel synthesis of 4
indoline from 2 that has higher yield than any known two-
step synthesis. Moreover this procedure replaces all
chemical reducing agents (e.g. heavy metal zinc, or
cyanide containing NaCNBH3) by environmental-friendly
catalytic hydrogenation.
Investigation of the N-alkylation reaction under flow
conditions using packed bed reactor
First, we investigated the N-alkylation of 4 by 1,2-
dibromoethane. The major drawbacks of this step are the
long reaction time (up to 4 days), the use of high excess
(20-60 equiv.) of the carcinogenic reagent, and the necessity to
use the high dilution technique. The latter two work against the
formation of the bis-adduct (6) by-product.
Higher temperatures under pressurized conditions in overheated
solvents, which is possible in flow chemistry, could decrease the
reaction time; we also wished to find an optimal set of reaction
parameters, where lower excess of reagent is sufficient.
Therefore, we investigated the N-alkylation reaction of 4 by 1,2-
dibromoethane using both heterogeneous (packed bed reactor)
and homogenous conditions (loop reactor).
Scheme 4. Heterogeneous continuous flow N-alkylation reaction using solid
inorganic base, or solid supported base. The Omnifit® column (10mm i.d. x
150mm) was filled either with 4.5 g of Cs2CO3:Na2SO4=1:1 (mixture of 2.25 g,
Cs2CO3 (28 equiv.) and 2.25
g Na2SO4,(65 equiv.)) or with Si-DMAP
(SiliaBond®, 5.0 g, 4,65 mmol, 19 equiv., 0.93 mmol g-1).
Acceptable conversion and selectivity values could be achieved
using 0.25 mL min-1 flow rate (Table 4, Entry 2) by this technique.
Due to the fact that this reaction requires stoichiometric amount
of base, the column filled with Silia-DMAP exhausts rapidly. In
case of a well-established reagent recovery system using
intelligent pumping[62] between multiple columns,[63] scaled-up
manufacturing can be managed, not economically. Furthermore,
regeneration of the bed and the use of solid supported reagents
are not common practice in industry.
After screening runs using pressurised microwave batch
conditions (See SI.), in which four solid inorganic bases (M2CO3,
where M = Na, K, Cs; and KOH) were tested, with or without
phase transfer catalyst (PTC); Cs2CO3 without PTC was found to
be the appropriate choice as a base. Syrris Asia column heater
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A 4 factor experimental design was proposed, in which the
independent variables were the temperature (100<T<140; [ºC]),
the residence time (15<tRes<45; [min]), excess of reagent
(10<1,2-dibromoethane<30; [equiv.]) and the dilution (50<c<100,
[mL g-1]).
Table 3. Results of the heterogeneous continuous flow N-alkylation reactions
using Cs2CO3 as a solid base.[a]
Entry
Flow rate
Conversion
(%)[b]
Selectivity
Selectivity
(mL min-1)
(5) (%)[b]
(355/357 m/z)[c] (%)[b]
Our design of experiment contained 2n-1+3 cases (where n
equals to the number of factors), which includes 8 experiments
for each of the four independent variables (corners of the cube)
and 3 more in the centre point (see SI.), to identify the deviation
of the results. The reaction mixtures were analysed by LC-DAD-
MS measurements and the independent variable’s effects were
examined on the dependent variables, which are the conversion,
selectivity, and their geometric mean (reduced dependent
variable: sq(C*S)).
1
2
0.5
86
86
16
21
57
63
0.25
[a] All experiments were performed as shown in Scheme 4.; [b] Determined by
LC-DAD-MS measurements; [c] Based on the literature[60,61] and the MS spectra
of the LC-DAD-MS measurements, the monobromo-compound with the 355/357
m/z is presumably the 2-bromoethyl 2-(2-ethoxy-2-oxoethyl)-2,3-dihydro-1H-
indole-1-carboxylate.
A purpose-built flow reactor system was assembled (Scheme
5.A.), in which the reactions were performed according to the
Table 4. Results of the heterogeneous continuous flow N-alkylation
reactions using solid supported reagent (Silia-DMAP) as a solid base.[a]
designed
experimental
procedure.
Similarly
to
the
Entry
Flow rate
Conversion
(%)[b]
Selectivity (5)
heterogeneous N-alkylation, a one pump setup was used,
because no reaction occurs in the presence of the base at room
temperature.
All reaction parameters’ impact was assessed by the Statistica
software (see SI.). The results showed that temperature has the
greatest impact on the reduced dependent variable. The most
interesting and valuable effect is that better results could be
achieved by using the same amount of reagent at higher
temperature (Scheme 5.B.).
(mL min-1)
(%)[b]
1
2
3
0.5
44
89
81
32
0.25
0.125
92
100
[a] All experiments were performed as shown in Scheme 4.;
[b] Determined by LC-DAD-MS measurements.
In other words, we were able to decrease the necessary amount
of carcinogenic reagent by elevating the temperature.
Using these findings, we could lower the amount of 1,2-
dibromoethane to 7 equivalents, which is almost one tenth of the
amount used in the original batch-wise procedure (60
equivalent) with conversion of 95% and selectivity of 91% (See
SI.).
Investigation of the N-alkylation reaction under flow
conditions using loop reactor
Truly continuous production can be achieved by homogeneous
N-alkylation in a loop reactor that is why we have investigated
this option too.
Further reduction of the excess of reagent was not feasible by
keeping the value of the reduced dependent variable over 93%
(See SI).
Moreover, almost complete conversion (95%) was achieved with
less than 30 minutes residence time, which is significantly better
than the batch reaction time (up to 4 days). The productivity
(space time yield) of the flow reaction system is ca. 200 times
better than the batch reaction conducted in the same reactor
volume. Using flow chemistry techniques makes the production
of 5 faster, safer, and more environmental-friendly.
The NH3 mediated ring closure reaction step (57) could not be
implemented under flow conditions, due to solubility issues of
the product and the inorganic co-product (ammonium bromide).
Although the original procedure gave good result, the work-up
needed further improvement. Finally, preparative column
chromatography was replaced by treating the crude product (7)
with hot EtOAc, resulting in pure 7 with good yield of 87% (see
SI).
Design of experiments (DoE) is
a widely used tool for
optimisation of the reaction parameters.[64–66] In this section we
would like to present further justification of the benefits of DoE
and its combination with flow chemistry.
This section is divided into four parts as follow. Firstly, we have
chosen the appropriate reagents (base, solvent) in the batch test
reactions. Secondly, reaction parameters that needed to be
optimised, was used in the DoE as independent variables.
Thirdly, the flow reactor system was assembled and the
designed experimentations were performed. After that, further
optimisation of the reaction parameters was carried out.
First, a few batch-wise test reactions were performed in order to
identify the suitable organic base. DIPEA seemed to be
applicable since TEA (triethylamine) forms an insoluble
hydrobromide salt co-product in acetonitrile during the reaction.
Although these pre-experiments are necessary to perform the
optimisation in flow, we have also found that the more base was
used, the less selective the reaction was. Therefore, we have
gained valuable information about the one reaction parameter
and we could establish the amount of the DIPEA in a minimum
value (1.15 equiv.) and decrease the number of independent
variables, and by that the number of experiments was needed.
With the completion of these test reactions the optimisation
could be started by the DoE.
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10.1002/ejoc.201700849
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This work is a further justification that flow
chemistry is
a
valuable technique. In the
development process of scaling-up the synthesis
of 4 and 5 indoline derivatives we profited from
the following benefits of flow chemistry technology
during our work:
There was no need for hydrogen cylinder in the
laboratory, since the hydrogen was generated in
situ from water in small amount, and was utilized
immediately in closed the system. Additionally, in
the N-alkylating step, the direct contact with
carcinogenic reagent was minimised, because
only preparing the stock solution and evaporation
of the reaction mixture were necessary. Therefore,
flow technology proved safer operation as
compared to the batch-wise reactions.
Significantly less time-consuming optimisation
was carried out using flow chemistry, which is
probably the most important factor in
pharmaceutical industry (after safety issues).
During scale-up studies in a batch-wise manner,
large amounts of substrate for test reactions are
necessary. On the contrary, using small amount
of substrates makes flow chemistry beneficial
considering its financial impact. In some cases
(e.g. catalytic hydrogenations), the results can be
extrapolated to batch reactions, which is also
beneficial in the scale-up procedure, when large
amount of intermediate is needed.
In summary, flow technologies significantly helped the
optimisation procedure of the 3 reaction steps and also opened
the path for utilization of this knowledge in continuous production
of these valuable intermediates.
Scheme 5. A, Homogeneous continuous-flow N-alkylation reaction using
DIPEA as base. B, The effect of temperature and the reagent excess on the
reduced dependent variable (sq(C*S)).
Conclusion
Experimental Section
We have developed a novel one-pot heterogeneous catalytic
hydrogenation procedure for the synthesis of an indoline
derivative (4). Continuous-flow heterogeneous hydrogenator
was used in the catalyst screen and optimisation procedure.
This reaction involves a consecutive nitro-group reduction and
cyclization to obtain the indole 3, which is further reduced in situ
into 2,3-dihydroindole (4). We have managed to perform the
reaction at atmospheric pressure of hydrogen, which is ideal for
scaled-up manufacturing, thus there is no need for pressurised
reactor. Chemical reducing agents (e.g. heavy metal zinc, or
cyanide containing reagent) was replaced by environmental-
friendly catalytic hydrogenation. The number of work-up
procedures, reaction times and the generated waste was also
reduced.
The N-alkylation reaction was also optimised using a purpose-
built flow reactor and design of experiments. Using the optimal
set of parameters allowed us to decrease the excess of the
carcinogenic 1,2-dibromoethane almost ten-fold. Moreover,
nearly complete conversion was achieved in a fraction of the
original reaction time. The productivity (space-time yield) of the
flow reactor system is ca. 200 times more as compared to the
batch reaction.
The experimental section contains only the flow procedures. All
the general information, analytical procedures and the known
batch-wise steps, which have only small changes as compared
to the literature, are presented as Supporting Information (SI).
For all isolated compounds (2-7) full characterisation by NMR
(1D and 2D) and HRMS and their spectra are available in SI.
General procedure for continuous catalytic hydrogenation
reactions in the H-CubeTM reactor (Scheme 2.)
To a 25 mL Erlenmeyer flask a 0.025M solution of ethyl 4-(2-
nitrophenyl)-3-oxobutanoate (2) (50 mg, 1 equiv., 0.2 mmol,
251.235 g mol-1) in acetic acid (8 ml) was added followed by
methanesulfonic acid (39 μL, 3 equiv., 0.6 mmol, 96.11 g mol-1,
1.48 g mL-1). The reaction mixture was pumped through the H-
CubeTM reactor with 0.5 mL min-1 flow rate, using palladium on
carbon (10 m/m%) catalyst cartridge (CatCart®), at 50 ºC. No
overpressure was adjusted on the back pressure regulator
(‘Full-H2’ mode). The CatCart® was then washed with acetic acid
for approximately 10-15 minutes and the collected reaction
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10.1002/ejoc.201700849
European Journal of Organic Chemistry
FULL PAPER
mixture was evaporated in vacuo. The residue was dissolved in
DCM (30 mL), washed with saturated Na2CO3 solution (15 mL)
and brine (15 mL). The organic phase was dried over anhydrous
Na2SO4, and evaporated in vacuo. The resulting crude product
was analysed by LC-DAD-MS. The same work-up procedure
was used in case of using acetic acid as solvent and/or
additional acid catalyst. When no acid was used as solvent or
catalyst, the extraction was omitted.
(SiliaBond®, 5.0 g, 4,65 mmol, 19 equiv., 0.93 mmol g-1) at flow
rates of 125-500 µL min-1. The back pressure regulator was
adjusted at 10-12 bar, and the temperature was set to 150 ºC.
The reaction mixture was collected and evaporated in vacuo.
The residue was analysed by LC-DAD-MS (See SI, Table S6).
General procedure for the homogeneous continuous flow N-
alkylation reaction using DIPEA as base (Scheme 5.)
All of the continuous flow hydrogenation reactions were
performed in H-CubeTM continuous-flow hydrogenation reactor
with 8 mL of reaction volume, in Full-H2 mode with the flow rate
of 0.5 mL min-1. (The results of the experiments can be found in
in the SI., Table S1-S3 respectively.)
A flow reactor was assembled consisting of an ultra-compact
high pressure dual piston pump with one working piston, one
auxiliary (Knauer Azura P 2.1S), a 30 mL tube reactor (Supelco
PTFE tubing, 1/8” o.d.; 0.085” i.d.) in oil bath (with two magnetic
stirrers) and an adjustable back pressure regulator (Zaiput
BPR10 - using nitrogen gas from a cylinder). The oil bath was
placed on a conventional hot plate (IKA® RCT basic). Oil bath
temperature was controlled and constantly monitored by a
precise IKA® ETS-D5 temperature controller. Supply lines
(Supelco PTFE tubing, 1/16” o.d.; 0.012” i.d.) and fittings (PEEK)
were purchased from Sigma Aldrich.
Procedure for the heterogeneous continuous flow N-
alkylation reaction using solid inorganic base (Scheme 4.)
A flow reactor was assembled consisting of an ultra-compact
high pressure dual piston pump with one working piston, one
auxiliary (Knauer Azura P 2.1S), an Omnifit® glass column
(10 mm i.d. x 150 mm), tempered by an Asia column heater
modul® (Sirrys Ltd.) followed by an adjustable back pressure
regulator (Zaiput BPR10 - using nitrogen gas from a cylinder).
Supply lines (Supelco PTFE tubing, 1/16” o.d.; 0.012” i.d.) and
fittings (PEEK) were purchased from Sigma Aldrich.
To a solution of 4 (100 mg, 1 equiv., 0.49 mmol, 205.253 g mol-
1) in acetonitrile (10 mL), DIPEA (100 µL, 1.15 equiv., 0.56 mmol,
129.25 g mol-1, 0.742 g mL-1) and 1,2-dibromoethane (1.26 mL,
30 equiv., 14.6 mmol, 186.87 g mol-1, 2.18 g mL-1) were added.
The reaction mixture was homogenised using ultrasonic bath
(Realsonic RS16) and pumped into the reactor at a flow rate of
667 µL min-1 (45 min residence time). The back pressure
regulator was adjusted at 18 bar and the temperature was set to
140 ºC. The reaction mixture was collected and evaporated in
vacuo. The residue was dissolved in DKM (30 mL), washed with
distilled water (30 mL) and brine (30 mL). The organic phase
was dried over anhydrous Na2SO4, and evaporated in vacuo.
The resulting crude product was analysed by LC-DAD-MS (See
SI, Table S8-S9).
To a solution of 4 (50 mg, 1 equiv., 0.24 mmol, 205.253 g mol-1)
in acetonitrile (5 mL), 1,2-dibromoethane (0.65 mL, 30 equiv.,
7.3 mmol, 186.87 g mol-1, 2.18 g mL-1) was added. The reaction
mixture was homogenised using an ultrasonic bath and pumped
into the column reactor, filled with 4.5 g of Cs2CO3:Na2SO4=1:1
(mixture of 2.25 g, 28 equiv. Cs2CO3, 6.87 mmol, 325.82 g mol-1;
and 2.25 g 65 equiv. Na2SO4, 15.8 mmol, 142.04 g mol-1) at flow
rates of 250-500 µL min-1. The back pressure regulator was
adjusted at 10-12 bar and the temperature was set to 150 ºC.
The reaction mixture was collected and evaporated in vacuo.
The residue was dissolved in DCM (30 mL), washed with
distilled water (30 mL) and brine (30 mL). The organic phase
was dried over anhydrous Na2SO4, and evaporated in vacuo.
The resulting crude product was analysed by LC-DAD-MS (See
SI, Table S5.).
Acknowledgements
R.Ö. thanks the Gedeon Richter Talentum and the Pro
Progressio Foundation for financial support. The authors also
thank members of our flow chemistry work team, especially P.
Bana for his valuable advices on the manuscript.
General procedure for heterogeneous continuous flow N-
alkylation reaction using solid phase supported base
(Scheme 4.)
Keywords: continuous-flow indoline synthesis • flow chemistry •
heterogeneous catalytic hydrogenation • N-alkylation
A flow reactor was assembled consisting of an ultra-compact
high pressure dual piston pump with one working piston, one
auxiliary (Knauer Azura P 2.1S), an Omnifit® glass column
(10 mm i.d. x 150 mm), tempered by an Asia column heater
modul® (Sirrys Ltd.) followed by an adjustable back pressure
regulator (Zaiput BPR10 - using nitrogen gas from a cylinder).
Supply lines (Supelco PTFE tubing, 1/16” o.d.; 0.012” i.d.) and
fittings (PEEK) were purchased from Sigma Aldrich.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Flow chemistry proved to be
a
Flow chemistry optimisation
valuable technique to improve the
synthesis of indoline derivatives. A
novel, one-step heterogeneous cataly-
tic hydrogenation was developed to
avoid the use of chemical reducing
agents. N-alkylation of the indoline
Róbert Örkényi,* Gyula Beke, Eszter
Riethmüller, Zoltán Szakács, János Kóti,
Ferenc Faigl, János Éles and
István Greiner
Page No. – Page No.
nitrogen was optimised using
a
purpose-built flow reactor and design
of experiment. Applying the optimal
set of parameters significantly redu-
ced the excess of the carcinogenic
reagent and the reaction time.
Environment-Friendly Synthesis of
Indoline Derivatives Using Flow
Chemistry Techniques
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