Divergent Multistep Continuous Synthetic Transformations of Allylic Alcohol Enabled by Catalysts Immobilized in Ionic Liquid Phases.

Article abstract of DOI:10.1002/cssc.201900107

Two individual catalytic platforms (metal- and organo-catalyzed) based on the use of an ionic liquid phase were successfully integrated for the synthesis of α-cyano-amine and cyanohydrin trimethylsilyl ethers from allylic alcohol. The right combination of continuous flow processes enabled access to the divergent preparation of two alternative and interesting intermediate compounds from the same starting material.

Full text of DOI:10.1002/cssc.201900107

Accepted Article
Title: Divergent multistep continuous synthetic transformations of allylic
alcohol enabled by catalysts immobilised in IL-phases.
Authors: Eduardo García-Verdugo, Santiago Luis, Edgar Peris, Raul
Porcar, Joaquin García-Álvarez, and Isabel Burguete
This manuscript has been accepted after peer review and appears as an
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201900107
Link to VoR: http://dx.doi.org/10.1002/cssc.201900107
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10.1002/cssc.201900107
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Divergent multistep continuous synthetic transformations of
allylic alcohol enabled by catalysts immobilised in IL-phases.
Edgar Peris[a], Raúl Porcar[a], Joaquín García-Álvarez[b], María Isabel Burguete[a], Eduardo García-
Verdugo*[a] and Santiago V. Luis*[a]
Abstract: Two individual catalytic platforms (metal- and organo-
catalysed) based on the use of ILs have been successfully integrated
and the right combination of continuous flow processes has enabled
access to the divergent preparation of two alternative interesting
intermediate compounds from the same starting material.
direct transfer of laboratory results to production; iii) reduction in
environmental impact; iv) improved safety; v) synthesis of new
high-value chemical entities; vi) intensification of the process.
Thus, smaller size systems can be used offering cost reduction
and higher productivity. Furthermore, the assembly of these
synthetic platforms in a divergent telescopic sequential fashion
can lead to systems able to produce molecules with wide
structural diversity.17,18
Introduction
Sustainability is not only a challenge, but also an opportunity to
radically transform synthetic processes to new emerging
technologies.1 In this context, there is a need to develop
alternative approaches mimicking natural processes that
integrate multiple and consecutive catalytic sequences.2,3,4,5
These transformations can be performed, to reduce their
environmental impact, under alternative reaction conditions using
neoteric solvents such as water, dimethyl carbonate, ionic liquids
(ILs) or supercritical fluids.6 Indeed, these solvents can contribute
to not only reducing human health problems and the environment
footprint of the synthetic process, but in some cases, to the
modification of the catalytic system enhancing its activity,
recyclability, stability and / or selectivity. At the same time, these
new synthetic methodologies should also face challenges related
to the paradigm shifts chemical industry is experiencing. These
include replacing discontinuous processes requiring multiple unit
operations by highly flexible and integrated continuous flow
catalytic processes.7,8,9,10,11 In this regard, the development of
multicatalytic platforms allowing sequential and controllable
processes is highly desirable. This can lead to complex syntheses
through reduced external intervention and minimal environmental
impact,.12,13,14,15,16 These platforms facilitate: i) greater
reproducibility of reactions; ii) easy scaling, which facilitates the
Figure 1. Divergent synthesis based on continuous flow catalytic platforms.
In this context, the main aim of the work has focused on the
divergent synthesis of -cyano-amines and cyanohydrin
trimethylsilyl ethers as depicted in Figure 1. Both families of
compounds are very useful synthetic intermediates for the
preparation of a wide variety of organic molecules with relevant
pharmacological properties.19,20 α-Cyano-amines can be obtained
by the three-component Strecker reaction using an aldehyde or
ketone, an amine and a cyanide source. In the absence of the
amine and with the selection of the proper catalyst the same
reactants can alternatively be transformed in cyanohydrin
trimethylsilyl ethers, which can easily be converted into
functionalized α-hydroxy acids, α-hydroxy aldehydes, β-amino
alcohols or other polyfunctional compounds.21 These two
reactions generally require HCN or alkali metal cyanides such as
KCN or NaCN as cyanide sources, which represents a serious
concern in terms of chemical hazards and waste treatment. To
overcome these problems TMSCN (trimethylsilyl cyanide) has
proven to be an effective, relatively safe, and easily handled
cyanide anion source.20 Both reagents use ketones or aldehydes
[a]
Mr. E. Peris, Dr. R. Porcar, Prof. M. I. Burguete, Dr. E.
García-Verdugo* and Prof. S. V. Luis*
Department of Inorganic and Organic Chemistry,
Universitat Jaume I,
Avda Sos Baynat s/n, E-12071, Castellón, Spain.
E-mail: cepeda@uji.es, luiss@uji.es
[b]
Dr. J. García-Álvarez
Departamento de Química Orgánica e Inorgánica, Instituto
Universitario de Química Organometálica “Enrique Moles” (Unidad
asociada al CSIC),
Facultad de Química,
Universidad de Oviedo,
E-33071 Oviedo, Spain
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cssc.201900107
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as starting materials that can be obtained from the isomerisation
of readily accessible allylic alcohols in a ruthenium-catalysed
process.22-25
In the search for such divergent platforms, here we report our
efforts to develop IL-based catalytic systems that can be
combined in a single continuous flow process to provide
alternatively two different families of intermediate compounds.
Such platforms allow the reduction in environmental impact and
enable the simple separation and reuse of the catalysts, providing
products not contaminated by traces of either catalyst or solvent.
In order to develop such a catalytic platform, four different Ru-
complexes were initially screened for the batch isomerisation of
1-octen-3-ol in an IL phase (Scheme 1). The reaction was
performed using a solution of the Ru-complexes in [BMIM][NTf2]
(0.5% weight) and employing a 1% mol loading of the catalyst with
respect to the alcohol. The reaction was monitored at 1 and 17
hours. Results obtained are summarised in Table 1. The Ru(IV)-
acetate complex Ru-4 was the organometallic catalyst showing
the highest activity, reaching > 99% of isomerisation yield
(scheme 1) in only one hour (TOF 100 h-1). The other Ru(IV)-
catalysts (Ru-2 and Ru-3) led to lower yields in one hour (67%
and 73%, respectively, Table 1), while the Ru(II)-complex (Ru-1)
showed almost no activity (< 10%) during the same period. The
three Ru-complexes afforded good to excellent isomerisation
yields after 17 hours. These results are in agreement with
previous results showing that Ru-4 was an efficient catalyst for
this reaction in both water (0.2 mol%, > 99%, 5 min, TOF 6000 h-
1) and [BMIM][BF4] (1 mol%, > 99%, 5 min, TOF 1200 h-1).25 The
lower activity observed here is most likely associated with the less
polar nature of [BMIM][NTf2].
Results and Discussion
Catalytic Platform 1. Ruthenium-catalysed isomerisation of
allylic alcohols into ketones: Ru-complexes are highly efficient
catalysts for the isomerisation of different allylic alcohols under
mild conditions and using neoteric solvents such as water,22 deep
eutectic solvents,23 or ILs like [BMIM][BF4].24,25 With this IL the
catalysts can be recovered during at least five consecutives
batches, using hexane as the extraction solvent, alothough the
catalyst showed a certain degree of deactivation upon recycling.
In order to develop a catalytic platform based on a Ru-catalyst
able to efficiently work for multiple cycles and allowing a simple
recycling, the combination of ILs with supercritical CO2 (scCO2)
provides a relatively simple and straightforward technological
solution.26 Generally, the IL-phase is used for the homogeneous
immobilisation of the catalyst (metal complexes, enzymes,
nanoparticles, etc), while the scCO2 phase is intended to favour
the delivery of substrates to the catalytic sites in the IL phase and
to facilitate the extraction and separation of the final products.
Very often, this combination allows optimised yields and
productivities by the fine tuning of the contact time of the
scCO2/IL-phases using either the pressure or the flow rates.
These catalytic platforms exclude the need for other additional
solvents and facilitate the isolation and separation of the products
from the catalyst, being able to work 24/7, requiring less work
force for operation, reducing the equipment size and maximising
productivity.
Table 1. Isomerisation of 1-octen-3-ol (5) in [BMIM][NTf2] with 1% mol of Ru
catalysts.[a]
Yield (%)[b]
Entry
Catalyst
1 h
< 7
67
17 h
> 99
> 99
87
1
Ru-1
2
3
4
Ru-2
Ru-3
Ru-4
73
> 99
--
[a] 2 mmol of 5. 1 gram of IL per mmol of reagent. 1% mol catalyst. Room
temperature. [b] Determined by GC.
Cat. Platform 1
CO2
Cl
Cl
Cl
Cl
Ru Cl
Cl Ru
Cl
Ru
Ru
Cl
Ru-1
Ru-2
pump-1
Cl
Cl
IL+cat
Ru
O
O
Ru N
Cl
N
H
pump-2
Ru-4
Ru-3
OH
O
[Ru]cat (1-4)
[BMIM][NTf2]
Figure 2. Schematic representation of the IL/scCO2 set-up used for the
isomerisation of 5 catalysed by Ru-2 and Ru-4.
5
6
Scheme 1. Model isomerisation reaction and Ru catalysts used.
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Based on these results, the reaction was studied using an IL/sCO2
system, enabling the semi-continuous production of the ketone
without the use of any additional organic solvent (Fig. 2). The IL-
phase was used simultaneously as reaction solvent and
homogenous media for catalyst immobilisation.27 In spite of the
higher activity of Ru-4, initial experiments were performed with
the dimeric complex Ru-2, which displayed a reasonable activity
and is commercially available. The schematic reactor set-up is
depicted in Fig. 2. The allylic alcohol was delivered by a HPLC
pump, while a refrigerated head scCO2 pump was used to feed
the CO2. Initially the flow rates were set to 0.1 mL/min of 1-octen-
3-ol (5) and 1.5 mL/min of CO2 at 75 oC and 10 MPa (Fig. 3). The
reaction was performed by first feeding 3 mL of 5 to the reactor at
a flow rate of 0.1 mL/min. After this, the system was filled with CO2
until reaching 10 MPa pressure and then, maintaining a constant
flow rate of 1.5 mL/min, samples were collected at different times
and analysed by GC. The initial samples showed a low degree of
isomerisation due to the short contact time of the allylic alcohol
with the complex. The degree of isomerisation increased with time,
reaching ca. 50% and 70% after 3 and 4 hours, respectively
(Cycle I, Fig. 3).
in the reactor was further extracted with Et2O confirming the
presence of an appreciable residual mass of the ketone (718 mg).
However, it is important to note that the product extracted with
scCO2 was a clear uncoloured oil without any trace of IL or
catalyst, while the product obtained by ether extraction showed
traces of the catalyst (coloured solution) and IL-phase (Fig. S.1).
Cycle III
Cycle I
Cycle II
100
90
80
70
60
50
40
30
20
10
0
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Extraction
Extraction
Extraction
0
1
2
3
4
5 20 22 24 26 40 42 44 46 48
TOS (hours)
Flow allylic-OH
Yield
Flow CO2
Figure 4. Results obtained for the isomerisation of 5 catalysed by Ru-4 in a
[BMIM][NTf2]/scCO2 system at 75 oC and 10 MPa (TOS: Time on stream).
Encouraged by these results, the catalyst Ru-4 was assayed
under similar conditions (0.27% mol catalyst loading, Fig. 4).
When the reactor was loaded with 2 mL of 5 and left to react
overnight, the extract obtained under these conditions (1.5
mL/min flow rate of CO2) showed full conversion of the allylic
alcohol into the corresponding ketone (Cycle II). In Cycle III, 6 mL
of 5, were fed (0.09% mol catalyst loading) for an overnight
reaction and again the extract showed > 95% conversion.
Noteworthy, cycles II and III altogether provided a TON of 1425
moles of 6 per mol of Ru-4.
Figure 3. Results obtained for the isomerisation of 5 catalysed by Ru-2 in a
[BMIM][NTf2]/scCO2 system at 75 oC and 10 MPa, (TOS: Time on stream,
measured since the feed of the allylic alcohol 5 starts). Ru(IV)-complex Ru-2
(154 mg) was dissolved in 10.5 g of [BMIM][NTf2] (1.5% by weight).
Catalytic Platforms
1 + 2. From allylic alcohols to
cyanohydrins: Once established that the Ru-4 / IL / scCO2
combination can efficiently transform the allylic alcohol 5 into
ketone 6, the further transformation of 6 into its cyanohydrin
trimethylsilyl ether (7) by reaction with TMSCN was evaluated
using an organocatalytic system (catalytic platform 2) using the
efficient catalytic system reported for us for this transformation
and based on supported ionic liquid-like phases.28 Thus, the
conversion of 6 into 7 was evaluated by directly pumping 6
through a fixed-bed reactor containing the catalyst 8 (Fig. 5).
Figure 6 summarises the results obtained using a flow rate of 0.1
mL/min of a mixture of one equivalent of ketone 6 and 1.2
equivalents of TMSCN at room temperature and under solvent
free conditions. Under this experimental set-up, 6 mL of the
These results, demonstrated the feasibility of the isomerisation
using the Ru complex immobilised in the homogenous liquid IL-
phase and the need for longer reaction times. Thus, the reactor
was charged again in a second cycle with 3 mL of 5 and the
reaction was left to proceed during 15 h before restarting the CO2
pumping an collecting the product for an additional 7 hours period,
achieving a 95% of conversion of the allylic alcohol into the
corresponding ketone (Cycle II; Fig. 3). An additional cycle was
repeated under the same conditions leading to comparable
results (93% of the product was ketone). However, the overall
mass balance indicated a relatively low extraction efficiency of the
product from the IL-phase. To evaluate this, the catalyst/IL-phase
ketone
6 (from platform 1) were transformed into the
corresponding cyanohydrin 7 with an excellent yield (99%).
Hence, the combination of these two systems can be used for the
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efficient synthesis of cyanohydrins starting from allylic alcohols
with productivities for both synthetic transformations of 1.08 Kg of
6ꞏg-1 hour-1ꞏL-1 and 3.8 Kg of 7ꞏg-1 cat 8ꞏhour-1 L-1 in terms of mass
of product obtained per gram of catalyst and per reactor volume
in one hour.
regard, the presence in 9a of the imidazolium fragments can
contribute to improve the catalytic activity provided by the Lewis
acid units.34,35,36,37 Such contribution is absent in the analogous
Sc-supported catalyst 9b, prepared from a commercially available
sulfonic polystyrene-divinylbenzene polymer (Amberlyst® 15).38
ILs
X
Spacer
cat
y
x
Polymer
N
N
OTf
OTf
SO2 Sc
OTf
N
N
y
Figure 7. PS-DVB supported Sc catalysts 9a and 9b.
Figure 5. Schematic representation of the set-up combining the catalytic
platforms 1 + 2 for the conversion of 5 into 7 catalysed by Ru-4 and 8.
Ph
R
O
NH2
HN
Sc-9a or Sc-9b
R
CN
+
TMSCN
+
Solvent
10
Yield (%)
13
14
(R = -H)
(R = -CH3)
10
11
(R = -H)
(R = -CH3)
12
100
Productivity
8
Scheme 2. Three-component benchmark Strecker reaction catalysed by 9a and
9b.
80
6
60
Both catalysts, 9a and 9b, were evaluated for the Strecker
reaction between benzaldehyde (10), aniline (12) and
trimethylsilyl cyanide (TMSCN) (Scheme 2).39 Under solvent free
conditions, benzaldehyde was smoothly converted in to the
corresponding α-aminonitrile in the presence of 9a (Entry 1, Table
2). Near quantitative yields were achieved when the reaction was
performed in the presence of an additional solvent (Entries 2-4,
Table 2) including the use of benign solvents like 2-methyl-
tetrahydrofuran (2-Me-THF) and dimethylcarbonate (DMC).
When the reaction was carried out in the presence of 9b using
either CH3CN or 2-Me-THF as solvents, yields (Entries 5 and 6,
Table 2) were significantly lower than those observed for 9a. This
difference was lower for the reactions carried out in CH3CN (99
vs. 84%, entries 2 and 5, Table 2). When the less reactive
acetophenone (11) was used instead of benzaldehyde the
differences were even more pronounced. While 9a afforded
moderate yields of 14 in 2-Me-THF (69%, Entry 8, Table 2) and a
20% yield in CH3CN (Entry 7, Table 2), the catalyst 9b was not
active for this reaction in none of the solvents evaluated (Entries
9 and 10, Table 2).
4
40
2
20
0
0
10
20
30
40
50
60
TOS (min)
Figure 6. Catalytic platform 2. Solventless conversion of the ketone 6 obtained
with the catalytic platform 1 into 7. Flow rate: 0.1 mL/min. 6:TMSCN 1:1.2 mol
ratio. Residence time: 20 min. 600 mg of catalyst 8 (TOS: Time on stream).
Catalytic Platforms 1 + 3. From allylic alcohols to -amino-
nitriles: The classical Strecker reaction is one of the simplest and
most economical methods for the synthesis of racemic -
aminonitriles.29 Polystyrene-immobilised catalysts, with either Ru
or Sc as the Lewis acid site, have been reported to promote this
three-component reaction of aldehydes, amines and TMSCN with
excellent conversions.30 However, analogous reactions with
ketones required significantly more reactive catalysts like the
polystyrene-supported gallium triflate (PS-Ga(OTf)2) reported to
provide the targeted α-aminonitriles in high yield and purity.31
Task-specific supported ionic liquid-like phases modified with
sulfonic groups (9a, Fig. 7) can be used to complex lanthanide
triflates, in particular scandium triflate (Sc(OTf)3).32,33 In this
The different behaviour of catalysts 9a and 9b highlights the key
role played by the presence of IL-like fragments in 9a. A
cooperative effect seems to exist between the scandium sites and
the IL-Iike units leading to a more efficient catalyst. The substrates
can be activated through hydrogen bonding with both the
imidazolium cation and the OTf- anion, which is not feasible in 9b.
As could be expected, this effect is more important in 2-Me-THF
as CH3CN can compete with TMSCN minimising the
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“electrophile–nucleophile dual activation” of the reactants with the
IL-like units.
pumped through a reactor packed with 0.85 g of 9a at 15 µL/min
the yield obtained was > 99% without any apparent activity decay
during more than 24 hours. Thereafter, the flow rate was
increased to 30 µL/min, 60 µL/min and 120 µL/min, still achieving
a very good activity (yield > 95%). Intermediate flow rate
reductions to 15 µL/min provided again yields > 99%. No leaching
of scandium was detected in the liquid phase by ICP-MS. These
results confirmed the stability of the catalyst 9a for the Strecker
reaction under flow conditions, with no detectable indication of
deactivation for more than 75 hours of continuous use. It is worth
mentioning that increasing the flow rate provided important
improvements in productivity. Thus, for the higher flow rate used
(120 µL/min) ca. 2.5 g of 13 per hour and gram of catalyst were
Table 2. Three-component Strecker reaction of benzaldehyde (10) or
acetophenone (11) with aniline (12) and TMSCN catalysed by 9a or 9b
(r.t).[a]
Entry
Catalyst
9a
Substrate
Solvent
Solvent free
CH3CN
R
Yield
89
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
11
11
-H
9a
-H
99
9a
2-Me-THF
DMC
-H
98
9a
-H
95
produced, keeping
a 95% conversion of the reactants.
9b
CH3CN
-H
84
Accordingly, with a small lab reactor loaded with ca. 2 g of catalyst
and using a flow rate of 0.12 mL/min, ca. 121 g of 13 could be
obtained in only 24 hours.
9b
2-Me-THF
CH3CN
-H
17
9a
-CH3
-CH3
-CH3
-CH3
20
9a
2-Me-THF
CH3CN
69
Cat. Platform 1
9b
< 5
< 5
CO2
9b
2-Me-THF
TMSCN
+
pump-6
PhNH2
[a] 1 eq benzaldehyde (10) or acetophenone (11) (5 mmol), 1 eq aniline (12)
(5 mmol), 1.2 eq TMSCN (6 mmol); 50 mg cat. 9a or 9b per mmol of 10/11;
1 mL of solvent per mmol of 10/11. Room temperature.
pump-1
pump-5
IL+cat
O
pump-2
6
120 µL min‐1
Cat. Platform 3
100
2.5
Yield (%)
Figure 9. Schematic representation of the reactor set-up combining catalytic
platforms 1 and 3 for the conversion of 5 into 15 catalysed by Ru-4 and 9a.
80
60
40
20
0
2.0
Productivity
1.5
1.5
60 µL min‐1
0.1 mL/min
0.01 mL/min
0.025 mL/min
100
0.025 mL/min
1.0
pre‐reactor
30 µL min‐1
15 µL min‐1
0.025 mL/min
Dynamic reaction
mixture
Pre reactor
15 µL min‐1
15 µL min‐1
0.5
0.5
75
0.0
0
3 4 5 6 7 8 9 2124 2730 33 45 48 51 54 68 70 72 74 76
TOS (hours)
50
Figure 8. Yield of 13 vs. time on stream (TOS) for the three-component Strecker
reaction of benzaldehyde (10), aniline (12) and TMSCN catalysed by 9a under
continuous flow. 1.5 M in 2-Me-THF, 0.850 g of catalyst 9a, 2.4 mL reactor
volume.
25
Yield (%)
Conv. (%)
Selec. (%)
0
0
275 550 825 1100 1375 1650 1925 2200 2475
TOS (min)
The long-term stability of the catalyst 9a was studied for the
continuous flow reaction between benzaldehyde, aniline and
TMSCN in 2-Me-THF. Flow conditions allow evaluating catalyst
stability in the absence of any physical abrasion of the polymeric
beads associated with their extensive use under batch
conditions.40 As shown in Fig. 8, when the reactants were initially
Figure 10. Results obtained combining the catalytic platforms 1 and 3.
Conversion, yield and selectivity of 15 vs. time on stream (TOS) for the Strecker
reaction of ketone 6, aniline (12) and TMSCN catalysed by 9a. 0.6 g of catalyst
9a, 1.9 mL reactor volume.
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pumping the mixture into the reactor (25 µL/min) similar results
were obtained in terms of yield (50-55%) but the selectivity was
clearly improved (ca. 90-92%).
P2O5
TMSCN
molecular sieve 4Å,
montmorillonite K-10
pump-6
Finally, a further improvement in the formation of the ketamine
was achieved using a new fixed-bed reactor packed with equal
amounts of two dehydrating agents P2O5 and 4Å molecular sieves
along with an acid montmorillonite (MM K10), which have been
reported to promote the preparation of imines under batch
conditions (Fig. 11).41,42 Thus, ketone (6) and aniline (12) were
mixed together under solvent free conditions for 12 hours and
then pumped through the first reactor heated at 60 oC (12 µL/min
flow rate) and the solution at the outlet of this reactor was mixed
with a flow of TMSCN (15 µL/min) before entering the second
fixed-bed reactor maintained at room temperature and packed
with 9a. Under these conditions, the yield was higher than 70%
and the selectivity excellent (> 95%). The final product (15) was
obtained with productivities of 26.5 g of 15 day-1 with only 0.6 g of
catalyst 9a. Thus, the combination of the catalytic platform 1
(metal-catalysed) and 3 (organo-catalysed) demonstrated to be
suitable for the telescoped preparation of -cyanoamines from
allylic alcohols.
pump-5
O
+ PhNH2
6
100
80
60
40
20
0
Selectivity (%)
Yield (%)
0
200
400
600
800 1000 1800 2000 2200
TOS (minutes)
Conclusions
Figure 11. Yield and selectivity for 15 vs. time on stream (TOS) for the Strecker
reaction of ketone 6, aniline (12) and TMSCN catalysed by 9a and set-up used
for the reaction. Reactor I: 1.2 g of 4Å molecular sieves, 1.2 g P2O5 and 1.2 g of
MMK10, 3.9 mL reactor volume. Reactor II: 0.6 g of catalyst 9a, 1.9 mL reactor
volume.
By the right combination of three different catalytic continuous
flow platforms, a divergent synthetic flow system for the
preparation of both the protected cyanohydrin 8 and the α-amino
nitrile 15 from the allylic alcohol 5 has been achieved. The long
term stability and the activity of each catalytic platform has been
evaluated and optimised. In all of the catalytic platforms ILs-
related species, as reaction media and / or as supported catalysts
(SILLPs) played a key role. The results obtained for the Strecker
reaction highlight the potential for catalytic applications of task
specific supported ionic liquid-like phases containing specific
functionalities (imidazolium-sulfonic acid in this case). The three
component Strecker reaction of a non-reactive aliphatic ketone
(6) has been achieved using a combination of dehydrating agents
and supported catalysts in telescoped consecutive flow mini-
reactors. Thus, the combination of allylic alcohol isomerisation
with the cyanosilylation and Strecker reactions, both for
aldehydes and ketones, gives access to a broad scope of
valuable synthetic building blocks as protected cyanohydrins and
α-amino nitriles with good yields in long-term stable continuous
flow procedures. It is worth mentioning that catalytic platforms 2
and 3 work under solventless conditions and that the neoteric
solvents scCO2 and [BMIM][NTf2] used in platform 1 are the only
solvents employed. Moreover, no purification step is needed
between catalytic platforms and therefore a waste minimisation is
reached in the whole process reported. Reasonable productivities
can be obtained for the different catalytic and multicatalytic
systems developed at the multigram scale (g-1 cat h-1).
The reaction of 6 with 11 and TMSCN was also evaluated under
solvent free batch conditions with catalyst 9a, affording the
corresponding α-aminonitrile 15 in 99% yield (no traces of 7 were
observed). This allowed to study the telescoped transformation of
the allylic alcohol 5 into the ketone 6 and this into the α-
aminonitrile 15 by combining catalyst 9a (catalytic platform 3) and
the Ru-4/IL/scCO2 system (catalytic platform 1) (Fig. 9). Thus, the
product extracted from the system 1 was pumped through a
catalytic fixed-bed reactor containing 0.6 g of 9a at 0.1 mL/min.
Results summarised in Fig. 10 show that initially modest yields
(ca. 40-45%) of product 15 were achieved, along with low
selectivities (80-85%) due to the formation of the corresponding
cyanohydrin (through direct reaction of 6 and TMSCN). An
increase in conversion accompanied by decay in selectivity (ca.
70%) was observed by reducing the flow rate to 25 L/min. Thus,
ketimine formation seemed to be the limiting factor. It must be
noted that the actual substrate/catalyst ratio in the flow system is
much higher than under batch conditions, which can additionally
promote the cyanosilylation of the unreacted aldehyde, reducing
selectivity. To improve imine formation before contacting catalyst
9a, the mixture of ketone and amine was pumped through a coil
reactor (0.2 mL, 8 min residence time) located before the fixed-
bed reactor loaded with 9a. However, under these conditions (25
µL/min flow rate), only a slight improvement in selectivity (75-
77%) and yield of 15 (50-55%) was observed (Fig. 10). A further
increase of the residence time (10 µL/min flow rate) did not
improve the results. When the ketone (6) and the aniline (12) were
mixed together under solvent free conditions for 12 hours before
Experimental Section
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Ruthenium complexes (Ru-1 to Ru-4) were obtained as previously
described,24 as well as SILLPs 8 and 9a-b.28,32
Financial support has been provided by MINECO of Spain
(CTQ2015-68429-R, CTQ2016-81797-REDC and CTQ2016-
75986-P) Generalitat Valenciana (PROMETEO/2016/071) and
the Gobierno del Principado de Asturias (Project GRUPIN14-
006). Technical support from SCIC-UJI is also acknowledged. E.
Peris thanks MICINN for the financial support (FPU13/00685).
Batch isomerisation of 1-octen-3-ol (5) into 3-octanone (6). 0.315 mL
(2 mmol) of 1-octen-3-ol (5) were dissolved in 2 g of [BMIM][NTf2]. 0.02
mmol (1% mol) of the ruthenium catalyst (Ru-1 to Ru-4) were added and
the mixture was left at 80 ºC under orbitalic stirring (220 rpm) for 1 hour.
Samples were periodically analysed by GC.
Batch three-component Strecker reaction of benzaldehyde (10) or
acetophenone (11), aniline (12) and TMSCN catalysed by 9a or 9b.
0.515 mL (5 mmol) of benzaldehyde (10) or 0.590 mL (5 mmol) of
acetophenone (11), 0.456 mL (5 mmol) of aniline (12) and 0.758 mL (6
mmol) of TMSCN were mixed. 5 mL of solvent (except solvent free cases)
and 250 mg of catalysts 9a or 9b were added (50 mg/mmol 10 or 11). The
mixture was stirred for 24 hours at room temperature. The samples were
analysed by 1H-NMR.
Continuous flow three-component Strecker reaction of benzaldehyde
(10), aniline (12) and TMSCN catalysed by 9a. The reactor was set-up
by introducing the SILLP-9a (850 mg) in a glass Omnifit® column 006RG-
10-10 (0.7854 cm x 10 cm), which was connected at its head to a
KdScientifics model of syringe pump. A 25 mL Hamilton syringe filled with
benzaldehyde (10), aniline (12) and TMSCN (1:1:1.2) was used. The
mixture of reagents was pumped through the catalytic bed at different flow
rates going from 0.015 to 0.12 mL/min. Aliquots were taken at constant
time intervals and analysed by 1H-NMR.
Continuous flow cyanosilylation reaction of 3-octanone (6). The
reactor was set-up by introducing the SILLP-8 (600 mg) in a glass Omnifit®
column 006RG-10-10 (0.7854 cm x 10 cm), which was connected at its
head to a KdScientifics model of syringe pump. A 25 mL Hamilton syringe
filled with 3-octanone (6) and TMSCN (1:1.2) was used. The mixture of
reagents was pumped through the catalytic bed at 0.1 mL/min. Aliquots
were taken at constant time intervals and analysed by GC.
Keywords: Ionic liquid • Supported ionic liquid • supercritical
CO2 • catalysis • continuous flow
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Electronic Supporting Information
Divergent multistep continuous synthesis enabled by
immobilised catalysts on IL-phases
Edgar Perisa, Raúl Porcara, Joaquín García-Álvarezb, María Isabel Burguetea,
Eduardo García-Verdugoa*, and Santiago V. Luisa*
a Universitat Jaume I, Departamento de Química Inorgánica y Orgánica, Campus del
Riu Sec, E-12071 Castellón, Spain
b
Universidad de Oviedo, Departamento de Química Orgánica e Inorgánica,
Instituto Universitario de Química Organometálica “Enrique Moles”, E-33071
Oviedo, Spain.
Table of Contents
1. scCO2 vs. Et2O extraction
2. Set-up used for 1-octen-3-ol (5) isomerisation in scCO2.
3. Kinetic study of the batch Strecker reaction of benzaldehyde (10), aniline
(12) and TMSCN catalysed by 9a.
4. Set-up used for the continuous flow three-component Strecker reaction of
benzaldehyde (10), aniline (12) and TMSCN catalysed by 9a.
5. Different set-ups/strategies used for the continuous flow three-
component Strecker reaction of 3-octanone (6), aniline (12) and TMSCN
catalysed by 9a.
6. NMR Spectra.
~ SI.1 ~
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1. scCO2 vs Et2O extraction
The product of the isomerisation of 1-octen-3-ol (5), 3-octanone (6), was extracted
with scCO2 in a continuous flow system. The catalytic ruthenium complex was
dissolved in the IL [BMIM][NTf2] inside the reactor where the reaction takes place.
1-octen-3-ol (5) was pumped inside the reactor and finally the product 3-octanone
(6) was extracted using scCO2. This allowed to extract only the product (colourless)
remaining intact the IL+Ru catalyst for the next catalytic cycle. In order to compare
and confirm the suitability of the choice of scCO2, an extraction with diethyl ether
was performed. As could be seen in Figure S.1, with diethyl ether not only the
product was extracted, but also part of the ionic liquid and the Ru catalyst dissolved
in it. The colouration of the colourless diethyl ether is a proof (see Figure S1).
1
Moreover, H-NMR studies were done (see Figure S2) confirming this hypothesis.
The top spectrum only contains the signals from 3-octanone (6), but the spectrum on
the bottom shows additional signals.
Figure S1. Et2O (left) vs scCO2 (right) extraction of the 3‐octanone (6)
~ SI.2 ~
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Figure S2. 1H‐NMR comparative study of the extraction of 3‐octanone with scCO2 or Et2O
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SI.3
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2. Set-up used for 1-octen-3-ol (5) isomerisation in scCO2.
Figure S3. Set‐up used for the continuous flow isomerisation of 1‐octen‐3‐ol (5) into 3‐octanone (6) using
scCO2
Figure S4. Parts of the pressure reactor used
~
SI.4
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3. Kinetic study of the batch Strecker reaction of benzaldehyde
(10), aniline (12) and TMSCN catalysed by 9a.
Figure S5. Kinetic study by 1H‐NMR (CDCl3) of the batch Strecker reaction of benzaldehyde (10), aniline (12)
and TMSCN. Conditions: 1 eq benzaldehyde (10) (5 mmol), 1 eq aniline (12) (5 mmol), 1.2 eq TMSCN (6 mmol),
250 mg cat‐9a, 5 mL 2‐MeTHF, r.t. The benzaldehyde singlet proton signal is observed at 9.9 ppm. The imine
intermediate singlet proton signal is observed at 8.4 ppm. The Strecker product singlet proton signal is
observed at 5.3 ppm. The evolution of the reaction with the appearing of the imine intermediate and posterior
disappearing could be observed.
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SI.5
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4. Set-up used for the continuous flow three-component Strecker
reaction of benzaldehyde (10), aniline (12) and TMSCN
catalysed by 9a.
Figure S6. Set‐up used for the continuous flow Strecker reaction of benzaldehyde (10). Syringe pump from
kdScientific and Hamilton 25 mL syringe were used. Glass Omnifit column 006RG‐10‐10 (0.7854 cm diameter
x 10 cm length) was used as reactor. The syringe was filled with a mixture of benzaldehyde (10), aniline (12)
and TMSCN (1:1:1.2) 1.5 M in 2‐MeTHF. The reactor was packed with 850 mg of SILLP‐9a. The samples were
collected in 12 mL glass vials.
~
SI.6
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5. Different set-ups/strategies used for the continuous flow three-
component Strecker reaction of 3-octanone (6), aniline (12) and
TMSCN catalysed by 9a.
Imine intermediate formation showed to be the yield limiting step in the continuous
flow Strecker reaction of the 3-octanone (6). One strategy tested to improve imine
formation was to pump the ketone and the amine together in a coil reactor (0.2 mL,
8 min residence time) set-up before the fixed bed reactor loaded with 9a (see Figure
S7). Increasing the contact time of ketone and aniline can favor the formation of the
ketamine prior to the action of the catalyst 9a.
Figure S7. Set‐up used to perform the Strecker reaction of 3‐octanone (6) with a previous coil
reactor to favor the imine intermediate formation. Syringe pump from kdScientific and
Hamilton 25 mL syringe were used. Glass Omnifit column 006RG‐10‐10 (0.7854 cm diameter
x 10 cm length) was used as reactor. Syringe was filled with a mixture of 3‐octanone (6),
aniline (12) and TMSCN (1:1:1.2). The coil reactor was 1 m length and 0.2 mL volume. Omnifit
column reactor was filled with 600 mg of SILLP 9a. Fractions were collected at the exit of the
column reactor using a Collector “GE Healthcare Frac‐920”.
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SI.7
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The second strategy used in order to push further the formation of the selectivity
limiting ketamine, was to build a previous dehydrating catalytic reactor to favour
the formation of the imine (see Figure S8).
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SI.8
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Figure S8. Set‐up used to perform the three‐component Strecker reaction of 3‐octanone (6) with a previous
dehydrating catalytic fixed‐bed reactor to favour the formation of the imine intermediate. Syringe pumps from
kdScientific and Hamilton 25 mL syringes were used. Glass Omnifit columns 006RG‐10‐10 (0.7854 cm diameter
x 10 cm length) were used as fixed‐bed reactors. Syringe 1 was filled with a mixture of 3‐octanone (6) and
aniline (12) (1:1). Syringe 2 was filled with TMSCN. Reactor 1 was packed with 4Å molecular sieves (1.2 g), P2O5
(1.2 g) and montmorillonite K10 (1.2 g). Reactor 1 was heated at 60 ºC with a i‐PrOH reflux. Reactor 2 was
packed with 600 mg of SILLP 9a. Fractions were collected at the exit of reactor 2 using a sample collector “GE
Healthcare Frac‐920”.
6. NMR spectra
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SI.9
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1H-NMR of 3-octanone (6)
1H-NMR (300 MHz, CDCl3) δ 2.38-2.30 (m, 4H), 1.50 (q, 2H), 1.26-1.18 (m, 4H), 0.98
(t, 3H), 0.82 (t, 3H)
1H-NMR data of 2-ethyl-2-((trimethylsilyl)oxy)heptanenitrile (7)
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SI.10
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1H-NMR (300 MHz, CDCl3) δ 1.80-1.68 (m, 4H), 1.50-1.44 (m, 2H), 1.35-1.31 (m,
4H), 1.03 (t, 3H), 0.91 (t, 3H), 0.23 (s, 9H)
1H-NMR data of 2-phenyl-2-(phenylamino)acetonitrile (13)
~
SI.11
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1H-NMR (300 MHz, CDCl3) δ 7.58 (dd, 2H), 7.47-7.40 (m, 3H), 7.26 (t, 2H), 6.89 (td,
1H), 6.76 (dd, 2H), 5.41 (s, 1H), 4.02 (bs, 1H)
~
SI.12
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~ SI.13 ~
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