Continuous flow ring-closing metathesis, an environmentally-friendly route to 2,5-dihydro-1H-pyrrole-3-carboxylates

Article abstract of DOI:10.1039/c7gc00235a

2,5-Dihydro-1H-pyrrole-3-carboxylates are important building blocks for the synthesis of high value pyrroles and pyrroloquinoline derivatives with interesting biological activities. The use of continuous flow allowed us to perform a key synthetic step, namely ruthenium-catalyzed ring-closing metathesis, with a residence time of 1 min at 120 °C. Dimethyl carbonate, a green solvent, was demonstrated for the first time to be an excellent solvent for this reaction in continuous flow. The continuous flow conditions proved to be general and the scale-up of this reaction was not only possible, but also highly efficient. Conversion of 10 grams of diene was realized in 37 minutes under continuous flow, yielding the desired heterocycle in 91% yield.

Full text of DOI:10.1039/c7gc00235a

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Bantreil, K. Grychowska, G. Umuhire Mahoro, E. Colacino, M. Pawlowski, J. Martinez, G. Subra, P. Zajdel
and F. Lamaty, Green Chem., 2017, DOI: 10.1039/C7GC00235A.
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DOI: 10.1039/C7GC00235A
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Continuous flow ring-closing metathesis, an environmentally-
friendly access to 2,5-dihydro-1H-pyrrole-3-carboxylates
Received 00th January 20xx,
Accepted 00th January 20xx
Marcin Drop,a Xavier Bantreil,b Katarzyna Grychowska,a Gilbert Umuhire Mahoro,b Evelina
Colacino,b Maciej Pawłowski,a Jean Martinez,b,c Gilles Subra,c Pawel Zajdela and Frédéric Lamaty*b
DOI: 10.1039/x0xx00000x
2,5-dihydro-1H-pyrrole-3-carboxylates are important building blocks for the synthesis of high value pyrroles and
pyrroloquinoline derivatives with interesting biological activities. The use of continuous flow allowed to perform a key
synthetic step, namely ruthenium-catalyzed ring-closing metathesis, with a residence time of 1 min at 120°C. Dimethyl
carbonate, a green solvent, was demonstrated for the first time to be excellent for this reaction in continuous flow. The
continuous flow conditions proved general and scale-up of this reaction was not only possible, but also highly efficient.
Conversion of 10 grams of diene was realized in 37 minutes under continuous flow, yielding the desired heterocycle in 91%
yield.
www.rsc.org/
S
Introduction
Olefin metathesis is becoming more and more used at the
industrial level for the synthesis of API (Active Pharmaceutical
Ingredients).1 For example, ring-closing metathesis (RCM) was
O
N
O
N
H
N
O
O
N
O O
OH
H
N
S
HN
N
HN
O
applied to the synthesis of ciluprevir (BILN-2061),
a
O
O
O
pseudopeptide inhibitor of HCV NS3 protease (Figure 1).2
Vaniprevir (MH-7009), a ciluprevir analog which synthesis also
requires a RCM step, is now evaluated in phase III clinical
trials.3 The six-membered ring oseltamivir phosphate, also
known as Tamiflu, and used in the treatment of influenza,
could also be synthesized thanks to a RCM process.4 The
seven-membered heterocyclic ring in SB-462795, a cathepsin K
inhibitor for the treatment of osteoporosis, was also obtained
using RCM as a key step.5
H
N
O
HN
O
N
O
O
O
O
Ciluprevir
Vaniprevir
O
N
NHAc
H
N
.
O
H2N
O
S
O
N
H3PO4
O
N
H
O
O
COOEt
In this context, beside our general interest in olefin
metathesis, specifically using greener solvents such as
poly(ethylene)glycol, glycerol and water,6 we recently
demonstrated that 2,5-dihydro-1H-pyrrole-3-carboxylates
could be obtained via ring-closing metathesis (RCM) using
SB-462795
Tamiflu
Figure 1. Pharmaceutical drugs synthesized using olefin metathesis
ethyl acetate as a solvent, and 1 mol% of NO2-Grela7 as
catalyst (Figure 2). These compounds were then converted
efficiently into the corresponding pyrroles, which are highly
versatile building blocks for biologically active compounds
(Scheme 1).8 We also demonstrated that the 2,5-dihydro-1H-
pyrrole-3-carboxylate 2a was a highly significant intermediate
in the synthesis of pyrroloquinolines,9 which behave as 5-HT6
receptor neutral antagonists. These compounds, displaying
pro-cognitive properties, might be useful in the treatment of
cognitive decline associated with Alzheimer’s disease and
cognitive disorders caused by genetic abnormalities.9a, 10 Ring-
closing metathesis on substrates similar to 1a, bearing an
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SIMes
Cl
Ru
SIMes
SIMes
Cl
Ru
Ts
Ts
Ring-closing
Metathesis
N
Cl
DOI: 10.1039/C7GC00235A
N
Ru
Ph
Cl
Cl
Cl
O
R
O
CO2Me
NO2
CO2Me
PCy3
iPr
NO2
O
HG-II, R = H
NO2-Grela, R = NO2
G-II
1a
2a
M51
SIMes
Cl
SIMes
SIMes
Cl
P(OiPr)3
Ph
Ph
Cl
Ru
Ru
Ru
Cl
O
O
O
O
Cl
Cl
Cl
S
L
N
M22
M52
M2, L = PCy3
M20, L = PPh3
M31, L = Py
NH
N
N
H
5-HT6 receptor antagonist
N
N
Scheme 1. Synthesis of high value molecules through metathesis9a
SIMes
Figure 2. Structure of the catalysts screened in this study
electron-withdrawing group on the olefin, is usually more
difficult than RCM of benchmark substrates such as diallyltosyl
amine.11 An improvement of the method consisted in
performing the reaction under microwave activation, which
each other in microfluidic systems, a perfect control of
stoichiometry,15 important for the selectivity of reactions, as
well as the control of exothermic reactions,16 could be
envisaged. In addition, versatile conditions, in terms of
temperature, pressure and flow rates, could be applied, to
facilitate optimisation process.
The literature reports dealing with ruthenium-catalyzed
metathesis under continuous flow conditions remain scarce17
and they focus mostly on the development of heterogeneous
catalysts.18 Since, for the moment, most heterogeneous
catalysts showed limited recyclability, our approach was to
focus on the development of environmentally friendly
conditions using easily available homogeneous catalysts.
11b, g,
h
allowed to reduce the reaction time to 5 min.9c,
However, scalability of the microwave conditions still
represents a huge challenge for this method. One efficient way
to circumvent this issue would be to use continuous flow
chemistry. Indeed, high temperature microwave synthesis
could be easily translated to continuous flow synthesis, since
both techniques allow efficient heating/cooling and generation
of a superheated solvent.12 In order to obtain reaction
conditions that could be applicable on even a larger scale, we
decided to focus on the RCM of 1a using continuous flow
chemistry. Continuous flow is more and more prevalent in
organic chemistry,13 providing several advantages over batch
synthesis.14 As low quantities of reagents are in contact with
Table 1. Optimization of the RCM continuous flow conditionsa
Ts
N
Ts
N
CO2Me
NO2
BPR
1a
CO2Me
NO2
+
Catalyst
Pump
(flow rate)
Heating coil
(residence time, T)
V = 5 mL
Back Pressure
Regulator
(100 psi)
2a
+
Solvent
Reservoir bottle
Res. Time
HPLC Conv. (%)
Entry
Solvent
T (°C)
(min.)
30
30
30
5
G-II
NO2-Grela
HG-II
94
95
94
94
M51
M52
14
22
10
7
M2
98 (84)b
23
M20
94
60
M31
25
23
M22
35
88
1
2
3
4
5
6
CH2Cl2
AcOEt
DMC
90
90
90
110
120
130
72
75
74
76
71
74
73
84
85
73
96
85
82
78
98
50
21
75
98
57
11
77
DMC
1
5
85
69
5
96
46
19
53
92
a
Reaction conditions: 1a (0.125 mmol), catalyst (3 mol%), solvent (1 mL), T, residence time; HPLC conversions of 1a into 2a are given. See Table S1 in SI for the
complete optimization. b 2 mol% catalyst were used.
2 | J. Name., 2012, 00, 1-3
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Ts
N
Flowrates
2.5 mL.min-1
Results and discussion
Ts
N
CO2Me
Reactions were performed using a Uniqsis Flowsyn system,
and reagents (substrates and catalyst) were dissolved together
in a single reservoir bottle prior to pumping into the residence
coil. To make sure that this methodology could be robust and
practically scalable, reactions were performed in air using ACS
Grade solvents, without degassing or drying. Second
generation commercially available catalysts, bearing N,N’-
bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene (IMes) as NHC
ligand, from different families, were tested (Figure 2).
Benzylidene (G-II19), boomerang-type (HG-II20 and NO2-Grela7),
NO2
1a (1 mmol)
in DMC (4 mL)
[1a] = 0.25M
BPR
CO2Me
NO2
120°C, 1 min
2a 96% HPLC conv.
83% yield
M2 (3 mol%)
in DMC (4 mL)
[M2]= 7.5mM
2.5 mL.min-1
Scheme 2. Continuous flow RCM of 1a using 2 pumps
thermal stability. Additionally, isomerisation of 1a was
observed when HG-II was used (up to 5%). Finally, a third
interesting set of conditions was found with catalyst M22,
which has a latent character that already proved to be useful
in RCM and polymerisation reactions.26, 30 At 130°C, catalyst
M22 gave 92% conversion within only 5 min reaction (Table 1,
entry 6).
22
“Scorpio”21 (M51 and M5223) and robust indenylidene24
(M2,25 M20, M31, M2226) catalysts were screened in the RCM of
compound 1a, with an o-NO2 phenyl ring, in dichloromethane
as solvent, at 90°C, with a residence time of 30 min and 3
mol% of ruthenium catalyst (Table 1, entry 1). Pre-catalysts
M51, HG-II, M2 and M20, which are more resistant to
temperature than G-II, NO2-Grela, M52 and M31, gave the best
HPLC conversions (up to 98%). Using M2 as catalyst, reducing
the catalyst loading from 3 to 2 mol% was detrimental to the
reaction. While decreasing the residence time to 20 min at
90°C resulted in a lower conversion, a concomitant increase of
temperature to 110°C allowed to obtain 94% conversion in
only 5 min.27 It is important to note that traces (up to 5%) of
isomerization of 1a, resulting from the formation of a
ruthenium hydride species,6f were detected in the crude
reaction mixtures; interestingly, the amount of isomerization
was below 1% when M52, M2, M20 and M31 were used.27
Although those conditions could be suitable for efficient RCM,
in a continuous effort to find environmentally friendly
conditions,6a-e we decided to search for a greener solvent than
dichloromethane. Previous studies in batch showed that ethyl
acetate and dimethyl carbonate (DMC) could be suitable
solvents for RCM.28 In addition, these solvents were classified
as non-toxic for the industrial synthesis of API.29 Since it was
an appropriate solvent for the RCM of 1a in batch,8 ethyl
acetate was first tested (Table 1, entry 2). Reactions using HG-
II, M51 and M22 gave interesting HPLC conversions (>85%) in
AcOEt, but results were not better than in dichloromethane.
DMC was then evaluated for the first time, to the best of our
knowledge, in continuous flow RCM. To our delight, catalysts
HG-II and M2 gave excellent results in the conditions tested.
Catalyst M2, which is a highly stable indenylidene-type pre-
catalyst, allowed to reach almost full conversion when
reactions were performed at 110°C for 5 min or at 120°C for 1
min (Table 1, entries 6-8). However, HG-II gave a lower
conversion at 120°C, probably because of a slightly lower
As stated above, reactions were run using one solution that
was pumped into the residence coil. Since catalyst
decomposition could occur rapidly when the catalyst is in the
presence of alkene substrate, through the formation of a
ruthenium methylidene species,31 reactions were also
performed using two separate solutions, one containing the
substrate 1a, the other one the catalyst. Catalysts M2, which is
temperature stable and gave the best results in DMC, and M31,
which activates faster and is thus more prone to
decomposition, were tested. Then, the substrate and catalyst
solutions were pumped at the same flow rate and mixed in a
coil heated at 120°C. After a residence time of 1 min, as for
Table 1, entry 5, conversions reached 96% and 19% with M2
and M31 resp., similar to the ones obtained in the one pump
experiments. This is demonstrating that decomposition, if
happening, does not distort the results obtained in Table 1
using a single reservoir bottle. Performed on a 1 mmol scale,
conditions with M2 using two separate solutions gave, after 1
min residence time at 120°C, filtration over silica, evaporation
and precipitation from diethyl ether, cyclized compound 2a in
83% yield (Scheme 2). Such result permits to envision the use
of an automated system, allowing the screening of substrates
or catalysts.
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the reservoir solution, after 37 min. Less than 5% conversion
was measured, demonstrating that the RCM process required
heating at 120°C in continuous flow.
View Article Online
DOI: 10.1039/C7GC00235A
Ts
N
Ts
N
CO2Me
BPR
R
1a-g
(1 mmol)
CO2Me
Ts
N
R
Ts
2a-g
Conditions A: 110°C, 5 min
Conditions B: 120°C, 1 min
M2 (3 mol%)
DMC (8 mL)
N
CO2Me
NO2
BPR
Ts
N
Ts
N
Ts
CO2Me
N
NO2
1a (10 g)
120°C
residence time 1 min
total reaction time 37 min
2a, 91% yield
M2 (3 mol%)
DMC (186 mL)
CO2Me
NO2
CO2Me
CO2Me
Cl
OMe
Scheme 4. Continuous flow RCM of 10g of 1a in 37 min.
2a
A: 87%
B: 91%
2b
A: 88%
B: 91%
2c
A: 79%
B: 88%
Since HG-II is one of the most used catalyst for API synthesis, it
was also evaluated on larger scale using conditions from Table
1, entry 4. Thus, on a 2 mmol scale with a residence time of 5
min at 110°C in DMC, cyclized compound 2a was isolated in
92% yield. Total reaction time was 16 min in this case. HG-II is
thus a good candidate for large scale RCM, even though, on
the same scale, total reaction time would be longer than with
M2. In addition, isomerization of 1a also occurred on this
scale; the undesired isomer was separated from 2a upon
precipitation, and then isolated and fully characterized.27
Ts
N
Ts
N
Ts
N
CO2Me
CO2Me
CO2Me
R
OMe
2d
A: 92%
B: 90%
2e, B: 52%
R = Cl, 2f, B: 68%
R = OMe, 2g, B: 81%
Scheme 3. Continuous flow metathesis of substrates 1a-g. Reaction conditions: 1a-g
(1.0 mmol), M2 (3 mol%), DMC (8 mL), 110°C, 5 min (conditions A) or 120°C, 1 min
(conditions B). Isolated yields are given.
In the next step, we investigated the utility of the developed
method for the RCM of compounds 1b-g, bearing different
substituents on the phenyl ring (Scheme 3). Two sets of
experimental conditions (A: 110°C for 5 min and B: 120°C for 1
min) were compared using substrates 1a-d to select the one
that would give the best results. Compounds 2a-d, bearing
respectively a nitro group, a chlorine atom, a methoxy group
or a hydrogen atom in ortho position of the phenyl ring were
obtained through RCM, after evaporation and precipitation
from diethyl ether. Experimental conditions B resulted in
shorter reaction time and provided slightly better yields.
Conditions B were thus selected and applied to substrates 2e-
g, bearing a chlorine atom or a methoxy group either in meta
or para position of the phenyl ring. Compound 2e, 2f and 2g
were isolated in 52%, 68% and 81% yield, respectively. In all
the cases, conversion was almost complete and neither
degradation nor intermolecular unwanted side reaction that
would have given dimer side-products were observed.
Moderate yields were mainly due to incomplete precipitation
during product isolation.27
Continuous flow is an innovative technology since, once
optimal conditions are found, they can be directly applied to
reaction scale-up. The RCM of 10g (23 mmol) of compound 1a
was thus attempted, using 3 mol% of M2 catalyst in DMC, with
a reaction coil heated at 120°C and a flow rate to ensure a 1
min residence time. Gratifyingly, 10g of substrate were
pumped into the continuous flow system within 37 min and
the cyclized dihydropyrrole 2a could be isolated in 91% yield,
which is exactly the same yield as obtained on a 1 mmol scale
(Scheme 4). In comparison, RCM of 15g of 1a in batch gave less
satisfying results.8 To confirm that the RCM reaction
proceeded in the reaction coil and not in the reservoir bottle
before pumping into the coil, the conversion was checked, in
Conclusions
We reported in this study a highly efficient continuous flow
protocol allowing the ring-closing metathesis of dienes 1a-g to
obtain 2,5-dihydro-1H-pyrroles 2a-g. We demonstrated that
dimethyl carbonate, an environmentally friendly solvent, was
an excellent solvent for the metathesis reaction in flow, which
could be completed within 1 min at 120°C. In addition, scaling-
up the reaction using continuous flow, from 1 to 23 mmol, did
not change the outcome of the ring-closing metathesis, and
yielded the cyclized compound 2a in 91% yield after 37 min.
Acknowledgements
We acknowledge the financial support of the University
Montpellier, CNRS, National Science Center, Poland, grant N°
2016/21/B/NZ7/01742, Institut Carnot Chimie Balard through
the ANR program N° 11 CARN 0001-01, the PHC Polonium
programme (French Embassy in Poland/ French Ministry of
Foreign Affairs and International Development). M.D. thanks
the Erasmus + Programme for fellowship. Umicore AG & Co.
KG is gratefully acknowledged for the gift of catalysts M2, M20,
M31, M51 and M52. Materia, Inc. is gratefully acknowledged
for the gift of catalyst HG-II.
Notes and references
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Ring---closing metathesis, realized for continuous flow using dimethyl carbonate as solvent, allowed
to convert up to 10g of dienes into important building blocks.