Fast and enantioselective production of 1-aryl-1-propanols through a single pass, continuous flow process

Article abstract of DOI:10.1002/adsc.200800108

A functional polymer 4, obtained by reaction of (R)-2-(1-piperazinyl)-1,1, 2-triphenylethanol with a Merrifield resin, has been loaded in a packed bed reactor and used as catalyst for the continuous enantioselective production of 1-arylpropanols by ethyla

Full text of DOI:10.1002/adsc.200800108

UPDATE
DOI: 10.1002/adsc.200800108
Fast and Enantioselective Production of 1-Aryl-1-propanols
through a Single Pass, Continuous Flow Process
a,b,
a,c
a
Miquel A. Pericàs, * Clara I. Herrerías, and Lluís Solà
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-977-920-222; e-mail: mapericas@iciq.es
Departament de Química Orgànica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
On leave from Departamento de Química Orgµnica. Instituto de Ciencia de Materiales de Aragón, Universidad de
Zaragoza – C.S.I.C., 50009 Zaragoza, Spain
b
c
Received: February 18, 2008; Published online: March 31, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A functional polymer 4, obtained by reac-
tion of (R)-2-(1-piperazinyl)-1,1,2-triphenylethanol
with a Merrifield resin, has been loaded in a packed
bed reactor and used as catalyst for the continuous
enantioselective production of 1-arylpropanols by
ethylation of aromatic aldehydes. The high catalytic
activity depicted by 4 allows the complete conver-
sion of the substrates with the use of stoichiometric
reagent ratios and unprecedently short residence
times (down to 2.8 min). In practice, a single-pass
operation can be used for all the studied aldehydes,
and productions of up to 13.0 mol/gh are recorded.
The sequential operation of the flow system for the
uninterrupted synthesis of a small library of enan-
tiopure 1-arylpropanols is also reported.
type of catalysis is the possibility of performing the
chemical reactions in a continuous mode in a flow re-
actor. In this manner, reaction and catalyst separa-
tion are carried out simultaneously.
In spite of these potential advantages, flow-through
processes have in general been restricted to the pro-
duction scale, and this can be probably ascribed to
the need for engineering effort for the optimization of
the different parameters controlling conversion and
enantioselectivity in this kind of processes.
[
2]
The amino alcohol-promoted, catalytic enantiose-
lective alkylation of aldehydes with diethylzinc is a
mechanistically well understood process that, for its
experimental simplicity, has been considered as a suit-
able benchmark for this approach. Thus, since the pio-
[
3]
neering work by Itsuno and FrØchet, some addition-
al polymer-supported amino alcohols have been intro-
duced for the enantioselective ethylation of alde-
Keywords: amino alcohols; asymmetric catalysis;
continuous flow process; diethylzinc additions; het-
erogeneous catalysis; ligand immobilization
[
4]
hydes. Although very high enantioselectivities have
been achieved in some instances, the primary goal of
developing a reasonably fast process has remained
elusive, and the reported catalysts and experimental
set-ups involve very long residence times and multiple
pass operation for the achievement of reasonable con-
Introduction
[
5]
version levels.
In recent years, we have been engaged in the
Increasing concerns on feedstocks and energy supply,
and on the sustainable management of the environ- design of functional amino alcohols that could be im-
ment, have led in recent years to a great interest in mobilized onto organic or inorganic supports with
the development of chemical processes involving a ra- minimal perturbation of the molecular regions where
[
6]
tional use of raw materials, the minimization of the catalytic activity resides. As a fruit of this effort,
energy consumption, and the avoidance of residue we have been able to develop polymer-supported
generation for the sake of more sustainable produc- amino alcohol ligands 1–4 that control the enantiose-
tion schemes. In this framework, catalysis represents a lective alkylation and arylation of aldehydes without
very attractive approach. In particular, enantioselec- any significant decrease in reaction rate or in enantio-
tive catalysis with heterogeneized chiral ligands has selectivity with respect to their homogeneous counter-
[
6a–e]
contributed to these goals due to its inherent advan- parts.
tages over comparable homogeneous catalysts: work- Polymer-supported amino alcohol 4, derived from
up avoidance and easy recovery and reuse of the cata- easily accessible enantiopure triphenylethylene oxide
[1]
[7]
lytic species. Moreover, an additional interest in this through a ring-opening strategy, stands out as the
Adv. Synth. Catal. 2008, 350, 927 – 932
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
927

Miquel A. Pericàs et al.
UPDATE
Results and Discussion
The continuous flow system used for the present
study (Figure 1) consists of a vertical, fritted and jack-
eted Omnifit glass column which contains the sup-
ported catalyst. This column is a low pressure liquid
chromatography column with a 10 mm bore size and
a 70 mm maximal bed height (5.5 mL), completely
filled with the swollen resin. During operation, the re-
agents are pumped in through the bottom end of the
column using two different piston pumps (one for al-
dehyde substrate/toluene and one for diethylzinc/tolu-
ene) in order to minimize the amount of background,
non-enantioselective addition reaction before contact
with the supported catalyst. A supply of dry toluene
allows for swelling of the resin at the beginning of the
process and washing of the channel system at the end
of the reaction. Isothermal operation is secured by cir-
culation of a cooling fluid at the desired operation
temperature through the column jacket.
When the reactor is completely filled with the swol-
len functional resin, isothermal piston flow operates.
Under these conditions, conversion is only deter-
mined by the feed composition, the reaction tempera-
ture, and the mean residence time of the reactants in
the reactor. The design equation for an isothermal
piston flow reactor in a stationary state is:
Scheme 1. Synthesis of polystyrene-supported ligand 4.
most readily available (Scheme 1), catalytically active
[
8]
and enantioselective among these functional resins.
In this paper, we describe the design of a new con- where W is the volume occupied by the catalyst, FA0 is
tinuous flow system based on functional resin 4, and the flow of the limiting reagent, X is the conversion
A
its optimization for the fast, single-pass ethylation of and r is the rate of the reaction. For a given amount
A
a diverse family of aromatic aldehydes with very high of catalyst (corresponding to a totally filled column),
conversion and enantioselectivity.
complete conversion can be achieved through the ma-
Figure 1. Continuous flow system used in the addition of Et Zn to aldehydes.
2
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 927 – 932

Fast and Enantioselective Production of 1-Aryl-1-propanols
UPDATE
nipulation of two parameters: flow rate and tempera- chiral ligand). This is the maximum amount of dry
ture. If enantioselectivity has to be simultaneously op- resin that can be swollen in the employed experimen-
timized, variation in temperature becomes severely tal set-up without provoking a flow collapse. With this
limited so that, in practice, only the flow rate allows increased catalyst amount, and by working at 08C,
ample variation. It is thus evident that only a highly very high conversions (95–97%) were achieved with a
active catalyst can allow the simultaneous achieve- constant enantioselectivity (94% ee). In order to im-
ment of high levels of conversion and enantioselectiv- prove the production of our system and to reach com-
ity in short residence times.
plete conversions, experiment 3 was carried out at
As an intial stage in this study, these parameters 108C. Gratifyingly enough, the steady state of the
were optimized for the addition of diethylzinc to ben- system was reached in ca. 1 hour, and (S)-1-phenyl-
zaldehyde (Table 1).
propanol was obtained with essentially complete con-
In all continuous flow experiments, the catalytic version (98%) and 93% enantioselectivity. As shown
resin was first swollen with dry toluene for one hour. in the last three entries in Table 1, an increase in the
À1
Next, the reactions were carried out by passing total flow rate to 0.288 mLmin did not exhibit any
through the column equal flows of a 0.9M solution of benefit. Therefore, the optimal conditions for the con-
benzaldehyde and a 1.1M solution of diethylzinc, tinuous flow addition of diethylzinc to benzaldehyde
both in toluene. Aliquots of the efluent at different in the employed experimental set-up were 108C, 1.5 g
À1
operation times were withdrawn to determine conver- of resin 4 and
a flow rate of 0.24 mLmin
À1
sion and enantioselectivity. Experiment 1, performed (0.12 mLmin of benzaldehyde solution). This flow
with a catalyst loading of 1.1 g, showed that rather rate involves a residence time of the reagents within
high conversions (ca. 90%) could be achieved at 08C the catalyst bed of only 9.8 min. For comparison
[
9]
À1
at a flow rate of 0.24 mLmin . On the other hand, purposes, the same level of conversion is achieved
when the reaction temperature was lowered to under stirred, batch conditions in 1.5 h with 4 mol%
[
6e]
À108C, conversion showed a significant decrease. For of the same polymer-supported catalyst.
experiment 2, we loaded the column with 1.5 g of With the experience gained in the optimization of
functionalized resin (corresponding to 0.975 mmol of the system for the case of benzaldehyde, we were in-
terested in examining the behaviour of a diverse
family of aromatic aldehydes in the continuous flow
process. In order to obtain comparative data, the se-
lected aldehydes were first tested under stirred batch
conditions using 6 mol% of resin 4 in toluene
Table 1. Simultaneous optimization of flow rate and reaction
temperature for the single-pass, continuous enantioselective
ethylation of benzaldehyde with resin 4.
(
Table 2).
[
a]
[b]
[b]
Experiment t
T
Resin Flow rate
Conv. ee
[%]
À1
Table 2. Batch catalytic enantioselective ethylation of alde-
hydes 5a–f.
[
h] [8C] 4 [g]
[mLmin ]
[%]
1
1
0
0
0
0
1.1
1.1
1.1
1.1
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.288
0.288
0.288
-
-
-
-
2
3
4
5
6
7
8
1
2
3
4
5
1
2
3
4
5
6
91
88
85
76
70
66
88
97
97
96
95
92
98
98
94
95
94
94
95
95
94
95
94
93
94
94
94
94
93
93
93
93
93
92
À10 1.1
À10 1.1
À10 1.1
À10 1.1
[a]
[a]
[a]
Substrate
Conv.
%]
Select.
[%]
ee
2
3
0
0
0
0
0
1.5
1.5
1.5
1.5
1.5
[
[%]
benzaldehyde (5a)
99
99
87
71
>99
99
98
93
91
92
78
2-fluorobenzaldehyde (5b)
4-fluorobenzaldehyde (5c)
2-(trifluoromethyl)benzalde-
hyde (5d)
10 1.5
10 1.5
10 1.5
10 1.5
10 1.5
10 1.5
76
4-(trifluoromethyl)benzalde-
hyde (5e)
4-cyanobenzaldehyde (5f)
98
99
90
89
>99
>99
[a]
Determined by GC with a Cyclodex-b column. The only
by-product was the corresponding benzyl alcohol, and
the configuration of the major product enantiomer was
(S).
[
[
a]
À1
Total flow rate (0.12 mLmin for each reagent).
Determined by GC with a Cyclodex-b column; (S)-1-
phenylpropanol is the major isomer.
b]
Adv. Synth. Catal. 2008, 350, 927 – 932
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
929

Miquel A. Pericàs et al.
UPDATE
[a]
Table 3. Continuous flow reactions with different substrates.
[
b]
[c]
[c]
[c]
Entry Substrate
Flow Rate
[
Res. Time
[min]
T
Conv.
Select.
[%]
ee
À1
mLmin ]
[8C] [%]
[%]
1
2
3
4
benzaldehyde (5a)
0.24
0.24
0.24
0.24
9.8
9.8
9.8
9.8
10
10
10
10
99
95
93
87
98
93
87
93
84
2-fluorobenzaldehyde (5b)
4-fluorobenzaldehyde (5c)
2-(trifluoromethyl)benzaldehyde
>99
>99
87
(
5d)
2-(trifluoromethyl)benzaldehyde
5d)
4-(trifluoromethyl)benzaldehyde
5e)
4-cyanobenzaldehyde (5f)
5
6
7
0.24
0.24
0.72
9.8
9.8
2.8
20
10
10
95
86
82
89
87
(
99
98
(
>99
>99
[
a]
The employed toluene solutions were 0.9M in aldehyde and 1.1M in Et Zn. A loading of 1.5 g of the functionalized resin
2
4
was used in each case.
[
[
b]
c]
Total flow rate (half from each reagent).
Conversion, selectivity and enantiomeric excess were determined by GC with a Cyclodex-b column. The only by-product
was the corresponding benzyl alcohol, and the configuration of the major product enantiomer was (S).
Next, experiments were performed to determine reaction times for the considered chemistry, the con-
the optimal flow rate and temperature conditions for tinuous flow conditions reported here completely sup-
each aldehyde in the continuous flow process. These press the mechanical deterioration of the resin beads
conditions were then used to carry out a preparative that unavoidably takes place under stirring in batch
experiment for each substrate, the output flow con- conditions, thus shortening the useful life-time of the
taining the reaction product being collected in every polymer-supported catalyst.
case for 3 h (Table 3). In the case of benzaldehyde
It is worth noting that, since the exploratory study
À1
(
5a), and using a flow rate of 0.24 mLmin , the in Table 1 was carried out with toluene solutions
system has a production of 4.4 mmol/h per gram of 0.9M in benzaldehyde and 1.1M in Et Zn, the sub-
2
resin 4, allowing the preparation of 2.61 g of pure (S)- strates in Table 3 were also tested using solutions of
1-phenylpropanol in a 3 h run. Especially significant is the same concentrations for homogeneity reasons.
the result obtained with 2-(trifluoromethyl)benzalde- However, it is evident that the use of a larger excess
hyde 5d (entries 4 and 5 in Table 3) since we could in- of Et Zn would lead to increased conversions or, con-
2
crease the conversion by more than 20%, the ee by versely, could allow increased flow rates. To test this
6% and the selectivity by 10% with respect to the hypothesis, we repeated the ethylation of the less re-
batch process. active 2-fluorobenzaldehyde (5b) by using a 0.5M so-
It is evident from the comparison of the results in lution of the aldehyde and a 1.1M solution of diethyl-
Table 2 and Table 3 that the continuous process and zinc at the same flow rate and temperature as in
the batch process lead to practically identical results Table 3. Gratifyingly, we observed a complete conver-
in terms of chemical selectivity (addition vs. reduc- sion (>99%), alcohol 6b being obtained with an ee of
tion) and enantioselectivity except for the case of 2- 89%. In the same manner, we were also able to in-
À1
(
trifluoromethyl)benzaldehyde, where the continuous crease the flow up to 0.72 mLmin without any drop
process leads to much better results. With respect to in the results. Thus, even for less reactive aldehydes
reaction times, in turn, the continuous process is the residence time can be decreased to 2.8 min (i.e.;
much faster, allowing in some cases a 24-fold reduc- the production increased to 7.4 mmol/gh) at the cost
tion of the reaction time. Thus, for the highly reactive of a higher diethylzinc consumption.
4
-cyanobenzaldehyde (5f), the flow rate could be in-
Finally, we also wanted to test the possibility of
À1
creased up to 0.72 mLmin . Under these conditions, using the developed flow system for the consecutive
the residence time was reduced to only 2.8 min and alkylation of different substrates, since this could be
the production of the system was 13.0 mmol/h per particularly important for the automatic synthesis of
gram of resin 4. Besides these unprecedented short small or medium sized libraries of enantiopure 1-aryl-
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 927 – 932

Fast and Enantioselective Production of 1-Aryl-1-propanols
UPDATE
Table 4. Consecutive additions of Et Zn to several aldehyde-
s.
Studies on the integration of the flow reactor with
more advanced robotic systems and application of
resin 4 to different enantioselective processes are now
underway in our laboratories.
2
[
a]
[b]
[b]
[b]
Substrate
t
[
Conv.
h] [%]
Select
[%]
ee
[%]
benzaldehyde (5a)
1
2
3
>99
>99
>99
>99
>99
>99
92
92
87
Experimental Section
2-fluorobenzaldehyde
(
5b)
Continuous Flow System Description and Details of
the Reaction Procedure
4
5
>99
88
99
>99
86
93
4
-fluorobenzaldehyde
(
5c)
The continuous flow system (see Figure 1) was set up
around a vertical fritted and jacket-thermostated Omnifit
glass column (10 mm of bore size and 70 mm of maximum
bed height) with a volume of 5.5 mL, which was loaded with
the functional resin 4. HPLC connectors allowed the
column to be connected to two Ismatec piston pumps using
6
85
>99
92
[
a]
The employed toluene solutions were 0.9M in aldehyde
and 1.1M in Et Zn. A loading of 1.5 g of the functional-
ized resin 4 was used. The combined flow rate was
0
2
À1
.24 mLmin , and the reaction temperature 108C. The
1
/16 in hard wall PTFE tubing. The two reagents and dry
resin was washed with toluene before adding the next al-
dehyde.
b]
toluene were kept in three independent bottles with connec-
tor caps with valves for an easy and inert connection to the
tubing. Two additional connectors, also with valves, allow
for washing of the channels with toluene and swelling of the
resin at the beginning of the process. All the solutions were
prepared under a dry inert atmosphere in a glove-box using
bottles with valves. During operation, nitrogen balloons
were used to equalize pressure through the whole system.
[
Conversion, selectivity and enantiomeric excess were de-
termined by GC with a Cyclodex-b column. The only by-
product was the corresponding benzyl alcohol, and the
configuration of the major product enantiomer was (S).
propanols (6). In practice, we used the experimental The reagent solutions (0.9M or 0.5M in aldehyde and 1.1M
Zn) were pumped through the column with identical
set-up in three consecutive reactions using three dif- in Et
2
ferent substrates. The results of this experiment have flows and the crude was collected through the upper end of
the reactor in a round-bottom flask under N . Aliquots or
been collected in Table 4. As can readily be seen, by
simply washing the functional resin with toluene after
the desired amount of a particular aldehyde has been
passed through, the next aldehyde can be converted
to the corresponding 1-arylpropanol with complete
chemical selectivity and levels of enantiocontrol iden-
tical to those observed for the individual experiments
in Table 3.
2
the crude were quenched by addition of saturated aqueous
NH Cl. The aqueous solution was extracted with CH Cl
4
2
2
and the organic phases combined, dried and concentrated
under vacuum. The results were determined by gas chroma-
tography (see Supporting Information).
General Procedure for the Addition of Diethylzinc to
Aldehydes under Batch Conditions using Resin 4 as
Catalyst
Conclusions
A suspension of the polymer bound catalyst 4 (6 mol%) in
toluene (0.13 mL) was smoothly stirred 30 min under N at
room temperature to swell the polymer. The corresponding
2
In summary, the use of resin 4 has allowed the devel-
opment of a most practical continuous flow system swollen resin was cooled to 108C and a solution of diethyl-
for the fast, enantioselective alkylation of aldehydes. zinc (0.25 mL, 0.27 mmol) was added. After 20 min, the al-
Due to the simple design and the very reduced set of dehyde (5a–f) (0.125 mmol) was added dropwise, and the re-
sulting mixture was kept under smooth stirring for 4 h. The
parameters parameters controlling conversion and
reaction was then quenched by the addition of saturated
enantioselectivity it can be easily optimized for any
individual substrate.
NH Cl solution (2 mL). The resin was removed by filtration,
4
the aqueous solution was extracted with CH Cl (3”2 mL)
2
2
In spite of the drawbacks usually ascribed to poly-
meric beads with respect to monolithic resins because
and the combined organic phases were dried and concen-
trated under vacuum. Conversion, selectivity and enantio-
meric excesses were determined from the crude mixture by
GC. Conditions of analyses and retention times of the (R)-
[
2a]
of uncontrolled fluid dynamics,
the (by far) fastest continuous process ever reported
resin 4 has led to
for the enantioselective ethylation of aldehydes under and (S)- isomers are given in the Supporting Information.
flow conditions. This very high catalytic activity,
which allows complete conversion under single pass
operation at reasonably high flow rates has permitted
the sequential operation of the flow system for the
Supporting Information
General experimental details. Characterization of 6a–6f,
1
3
1
uninterrupted synthesis of a small library of enantio- copies of C and H NMR spectra of 6a–6f are given in the
pure 1-arylpropanols.
Supporting Information.
Adv. Synth. Catal. 2008, 350, 927 – 932
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
931

Miquel A. Pericàs et al.
UPDATE
Acknowledgements
b) P. Hodge, D. W. L. Sung, P. W. Stratford, J. Chem.
Soc. Perkin Trans. 1 1999, 2335–2342; c) M. I. Burguete,
E. García-Verdugo, M. J. Vicent, S. V. Luis, H. Penne-
man, N. Graf von Keyserling, J. Martens, Org. Lett.
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Altava, M. I. Burguete, E. García-Verdugo, S. V. Luis,
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This work was funded by MEC (Grant CTQ2005–02193/
BQU), DIUE (Grant 2005SGR225), Consolider Ingenio
2010 (Grant CSD2006–0003), and ICIQ Foundation.
[
6] a) A. Vidal-Ferran, N. Bampos, A. Moyano, M. A. Peri-
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[
[
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Adv. Synth. Catal. 2008, 350, 927 – 932