Continuous proline catalysis via leaching of solid proline

Article abstract of DOI:10.3762/bjoc.7.197

Herein, we demonstrate that a homogeneous catalyst can be prepared continuously via reaction with a packed-bed of a catalyst precursor. Specifically, we perform continuous proline catalyzed α-aminoxylations using a packed-bed of L-proline. The system relies on a multistep sequence in which an aldehyde and thiourea additive are passed through a column of solid proline, presumably forming a soluble oxazolidinone intermediate. This transports a catalytic amount of proline from the packed-bed into the reactor coil for subsequent combination with a solution of nitrosobenzene, affording the desired optically active α-aminooxy alcohol after reduction. To our knowledge, this is the first example in which a homogeneous catalyst is produced continuously using a packedbed. We predict that the method will not only be useful for other L-proline catalyzed reactions, but we also foresee that it could be used to produce other catalytic species in flow.

Full text of DOI:10.3762/bjoc.7.197

Continuous proline catalysis via leaching
of solid proline
Suzanne M. Opalka1, Ashley R. Longstreet2 and D. Tyler McQuade*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1671–1679.
1Department of Chemistry and Chemical Biology, Cornell University,
doi:10.3762/bjoc.7.197
Ithaca, NY 14853 and 2Department of Chemistry and Biochemistry,
Florida State University, Tallahassee, FL 32306
Received: 09 September 2011
Accepted: 14 November 2011
Published: 14 December 2011
Email:
D. Tyler McQuade* - mcquade@chem.fsu.edu
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
*
Corresponding author
Keywords:
aminoxylation; flow chemistry; heterogeneous catalysis; packed-bed
microreactor; proline/thiourea catalysis
© 2011 Opalka et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Herein, we demonstrate that a homogeneous catalyst can be prepared continuously via reaction with a packed-bed of a catalyst
precursor. Specifically, we perform continuous proline catalyzed α-aminoxylations using a packed-bed of L-proline. The system
relies on a multistep sequence in which an aldehyde and thiourea additive are passed through a column of solid proline, presumably
forming a soluble oxazolidinone intermediate. This transports a catalytic amount of proline from the packed-bed into the reactor
coil for subsequent combination with a solution of nitrosobenzene, affording the desired optically active α-aminooxy alcohol after
reduction. To our knowledge, this is the first example in which a homogeneous catalyst is produced continuously using a packed-
bed. We predict that the method will not only be useful for other L-proline catalyzed reactions, but we also foresee that it could be
used to produce other catalytic species in flow.
Introduction
Continuous flow chemistry [1-3], performed in small dimen- of solids to a flow reactor is particularly difficult as most pumps
sion tubing or channels, differs from batch chemistry in that function poorly with even small particulates, which in turn can
mixing and heat transfer are significantly faster and can be result in channel clogging. Although the use of solids in flow
precisely controlled. In addition, continuous technology enables has been the topic of a number of recent papers, they have
the generation and immediate use of unstable or hazardous focused on overcoming the challenges associated with the
intermediates [4-9] as well as the combination of many reac- introduction and suspension of solid reagents and starting
tions in series to achieve multistep synthesis [9-13]. Despite the materials [14-18]. An area that has received less attention is the
many favorable attributes of micro- and mesoflow reactors, the continuous use of solid catalysts (and catalyst precursors) that
continuous use of solids remains challenging. The introduction only partially or slowly dissolve into or react with the solution.
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Figure 1: Methods for catalyst use in flow.
(
See Figure 1 for a comparison of solid catalysts that are as well as in proline catalysis [36,37]. This prompted us to
used in flow.) Proline is an example of such a catalyst [19] consider new strategies for the implementation of proline
others include zero-valent transition metals, many solid acid in a continuous-flow system without resorting to proline
(
catalysts, and other secondary amine catalysts). Proline is often analogues or tethered catalysts [38-40]. Achieving this goal
added to a reaction mixture as a solid, and only a few mole would enable us and others to perform proline-catalyzed
percent dissolves into solution at any given time. Since proline reactions, aldol [41-43] and Mannich [42] reactions as well
is fairly inexpensive, it is an attractive test catalyst for the as α-functionalizations (α-aminoxylation, α-amination or
design of new methods to utilize solid catalysts or catalyst α-halogenations), continuously [44].
precursors in flow.
We hypothesized that the proline-catalyzed α-aminoxylation
Current strategies involving the use of catalysts with limited could be implemented in flow with reasonably short residence
solubility in flow rely on them being supported on resins or times using a urea additive. Many researchers, including us
polymers (Figure 1A and B). This can be an attractive method [36,37], have found that urea [45] additives increase the rate of
as the catalysts are often easily recycled [20-24]. Finding a suit- various proline-catalyzed reactions [46-50]. The role that ureas
able solid support for a reaction, however, can prove time- play remains unclear, and a number of hypotheses have been
consuming and expensive. In addition, care must be taken to suggested. Initially, researchers gathered 1H NMR, UV, and
identify a support that provides both high activity for the cata- fluorescence data to show that ureas enhance the solubility of
lyst and appropriate swelling properties to enable adequate mass proline through a host–guest interaction between the urea and
transport (often the best solvent for the resin will not be the best proline carboxylate: A substrate-independent model [49,50].
for the reaction) [25-29]. With researchers becoming increas- However, it has been proposed that substrate–urea–proline
ingly interested in developing continuous-flow processes, the interactions may also contribute to the rate enhancement [50].
rapid assessment of catalyst conditions necessary for potential Our group observed that a urea tethered to a tertiary amine
synthetic routes requires a simple approach to deal with limited- increases the rate of a number of batch reactions, including the
solubility catalysts.
α-aminoxylation reaction [36,37]. For the α-aminoxylation reac-
tion, we proposed that the urea promotes formation of the active
We have both a long-standing interest in the production, use enamine intermediate through breakdown of the putative oxazo-
and management of solids [30-33] and reactions [34,35] in flow lidinone intermediate: A substrate-dependent model. Here, we
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Beilstein J. Org. Chem. 2011, 7, 1671–1679.
report that a packed-bed of solid proline can be used to create a To test our hypothesis, we used a Vapourtec R series reactor
homogeneous catalyst, and we use this system to perform system [51] consisting of HPLC pumps for solvent and reagent
continuous α-aminoxylations. Not only do we illustrate a unique inputs, a low-temperature tube reactor containing a glass
use of catalysts in flow, but we provide additional insight into column packed with 1 g of proline, and a low-temperature
the role of additives in proline-catalyzed reactions.
10 mL PFA coil-tube reactor in which each reagent stream
could be precooled prior to mixing (Figure 2). As we demon-
strate below, the success of our experiments depended on the
Results and Discussion
In our previously published batch work, we found that the ability of the system to heat, or cool, the packed-bed and the
combination of L-proline and bifunctional urea 3a greatly accel- reaction coil independently of one another.
erated the rate of α-aminoxylation (Scheme 1). It was shown
that a longer linker between the urea and amine functionality Using this device configuration, experiments were performed to
enhanced the rate of reaction (see Supporting Information of identify the conditions that favor the reaction between the alde-
[
37]). The rate enhancement enabled the reaction to be hyde and the proline packed-bed in order to yield enough
performed in greener solvents such as ethyl acetate instead of soluble oxazolidinone catalyst to support rapid α-aminoxyla-
the more commonly used chloroform. We have a long standing tions. We were particularly interested to determine which sub-
interest in the conversion of the reaction into a continuous strate and additive components were necessary to dissolve the
process, but recognized that the solubility of proline would solid proline. Since the inherent solubility of proline in ethyl
hinder its use in flow. To circumvent this problem, we envi- acetate is very low, we extrapolated that this solvent alone
sioned using a cartridge of solid proline as a precatalyst source, would be insufficient to dissolve enough catalytic proline
whereby the flow of a combination of solvents, reactants and [37,52]. Furthermore, we knew from our previous batch work
cocatalysts through the packed-bed would produce the active, that a urea additive would be beneficial to provide reaction rates
homogeneous, oxazolidinone catalyst.
suitable for use in flow [37].
Scheme 1: Prior results for batch α-aminoxylation reaction.
Figure 2: General reactor setup. A) A glass Omnifit column is packed with 1 g of proline. B) The column is then placed in-line with a 10 mL PFA coil-
tube reactor. C) The components are connected to HPLC pumps for solvent and reagent inputs. The reactor is controlled by a computer in order to
program the timing of the reagent and solvent inputs and fraction collection.
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Beilstein J. Org. Chem. 2011, 7, 1671–1679.
Therefore, various combinations of reagents and catalysts by the addition of thiourea 3b. Consequently, it appears that our
entering the packed proline column were investigated. For our observed rate enhancements with thiourea 3b cannot be attrib-
initial experiments we selected a 15 min coil residence time and uted to a model involving only urea–proline interactions
temperature of 0 °C for both the column and the coil, based on resulting in enhanced solubility, and that substrate–urea–proline
our prior knowledge of the reaction in batch. We began by interactions are responsible for the observed reactivity when
determining the necessity of a urea cocatalyst. We were using this combination of thiourea, substrate and proline.
surprised to find that when hexanal alone was passed through
the column and combined with nitrosobenzene in the coil, the We were delighted to find that further increasing the residence
desired product was not detected by crude 1H NMR analysis time of the coil to 20 min with the same reagent configuration
(
Table 1, entry 1). This indicates that, with this reactor setup, resulted in 69% yield (Table 2, entry 2). For further experi-
the reaction is too slow without a urea additive to be a viable ments, we therefore used a setup in which a thiourea/aldehyde
method. Additionally, flowing thiourea 3b (0.047 M in EtOAc) stock solution was passed through the proline packed-bed
through the proline packed-bed prior to combination with the before entering the coil and reacting with nitrosobenzene.
other reaction partners resulted in no detectable reaction
(
Table 1, entry 2). This shows that thiourea 3b alone cannot As all of the reactions performed in Table 1 had the same resi-
solubilize enough proline to support the reaction. When hexanal dence time and temperature, the yield can be used as a rough
alone, however, was passed through the column and combined proxy for reaction rate. We conjecture, based on our prior work
with the remaining reagents in the coil (including thiourea 3b) in this area, that the aldehyde slowly reacts with solid L-proline
the reaction produced 27% yield and 99% ee (Table 1, entry 3). in the cartridge to form the soluble oxazolidinone intermediate
This indicates that the aldehyde alone can react with solid (Figure 3, part C), leaching proline out of the column and into
proline to produce a reactive homogeneous catalyst. However, the coil for reaction with nitrosobenzene. The increased yield
when both thiourea 3b and hexanal were used in the same stock observed when both hexanal and thiourea 3b were passed
solution and passed through the column the reaction attained through the proline-bed suggests that more catalyst was drawn
4
3% yield with 98% ee (Table 1, entry 4). This increase in into the solution, resulting in a faster reaction rate. In our prior
yield, relative to when hexanal alone was passed through the batch experiments, we proposed that the urea aided the break-
column, suggests that the rate of proline leaching is enhanced down of the oxazolidinone intermediate (Figure 3, part C) for
Table 1: Screening of the reactor setup.
entry
reagent bottle A
reagent bottle Ba
yield (%)
ee (%)b
1
2
3
4
hexanal
nitrosobenzene
nrc
na
na
99
98
thiourea 3b
hexanal
nitrosobenzene + hexanal
nitrosobenzene + thiourea 3b
nitrosobenzene
nrc
27d
43d
hexanal + thiourea 3b
aEntry 4 also contained dodecane as an internal standard. bDetermined by chiral HPLC. cnr = no reaction as determined by 1H NMR analysis of the
crude reaction mixture after reduction. dIsolated yield (due to instability of the aldehyde, products were reduced to their corresponding 2-aminooxy
alcohols in batch, prior to isolation). na = not applicable. See Supporting Information File 1 for detailed reaction conditions.
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Beilstein J. Org. Chem. 2011, 7, 1671–1679.
Table 2: Screening of temperature and residence time.
entry
column temperature (°C)
coil temperature (°C)
residence time (min)
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
0
0
15
20
15
20
10
20
20
25
20
20
20
20
43
69
82
85
61
84
86
81
84
75
66
68
98
98
98
98
98
98
98
98
98
98
98
98
0
0
0
15
15
15
10
5
0
0
0
0
0
5
−5
5
5
10
11
12
5
10
20
5
5
aIsolated yield (due to instability of the aldehyde, products were reduced to their corresponding 2-aminooxy alcohols in batch, prior to isolation).
bDetermined by chiral HPLC. See Supporting Information File 1 for detailed reaction conditions.
Figure 3: Schematic of the reactor setup. As the starting aldehyde and thiourea 3b (A) enter the proline packed-bed (B) an oxazolidinone intermedi-
ate is formed, drawing the proline into the solution (C). Upon precooling in a reactor coil (E) the intermediate is mixed with nitrosobenzene (D). Prior to
exiting, ethyl acetate is added to dilute the reaction (F) and product is collected into vials (G) for further reduction, work-up, and isolation.
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Beilstein J. Org. Chem. 2011, 7, 1671–1679.
rapid reaction with nitrosobenzene, and this thesis is supported 61% yield (Table 2, entries 4 and 5). We found that as the coil
by our observations reported herein.
temperature was decreased from 15 to 10 and then to 5 °C the
yield corresponding to a 20 min residence time remained steady
With evidence for adequate proline transport into the coil, opti- (Table 2, entries 4, 6, and 7). A further reduction to 0 °C,
mization experiments were performed. Based on previously however, showed a decrease to 69% (Table 2, entry 2). At each
published studies on the α-aminoxylation, we believed that of these temperatures the enantioselectivity remained high.
careful control of the temperature would be necessary to avoid
the formation of byproducts and to realize high enantio- Next, the packed-bed temperature was varied to determine how
selectivity. The forced convection cooling system facilitated temperature influenced the formation of the active catalyst
easy and precise temperature control of both the column and species from hexanal, proline, and thiourea 3b. We found that at
coil independently. Reported byproducts include the self-aldol column temperatures less than 0 °C the reaction performed well
product, the formation of azoxybenzene from the reaction of the (Table 2, entries 7 and 9). As the temperature was increased to
desired product with nitrosobenzene, and finally azobenzene by 5, 10, and 20 °C the yield dropped and was 68% at 20 °C
product disproportionation [53-55]. Byproduct suppression is (Table 2, entries 10, 11, and 12). Therefore, for further experi-
both solvent and temperature dependent. Hayashi reported that ments we chose a column temperature of 0 °C and a coil
when the reaction is performed at room temperature in acetoni- temperature of 5 °C with a 20 min residence time. It is clear,
trile with 30 mol % proline, the reaction is complete in 10 min, however, from the parameters investigated, that when simple
but achieves only 29% yield [55]. MacMillan, however, found sterically unencumbered aldehydes are used this reaction works
the reaction to be rapid in chloroform at room temperature with well under a variety of conditions.
7
8% yield, using 10 mol % proline [56]. In addition, our prior
batch work with urea 3a in ethyl acetate found that the To assess the long term stability and activity of the L-proline
α-aminoxylation of hexanal worked well at 0 °C with 5 mol % packed-bed, the system was run continuously for over 4 h. After
proline in 2 h. Therefore, we studied the impact of both the the system reached equilibrium, 20 mL fractions of product
packed-bed and reaction-coil temperature on the enantio- were periodically collected, reduced and purified. The data
selectivity and product yield.
shown in Figure 4 indicate that the reaction is stable over this
period of use. During the ~5 h collection period, assuming an
To begin with, we kept the column temperature at 0 °C and average yield of 78%, approximately 9.8 g was produced. Over
increased the coil temperature to 15 °C. Under these conditions the entire run 80 mL of hexanal/thiourea 3b stock solution was
a 15 min residence time provided 82% yield (Table 2, entry 3). passed through the column. Upon completion of this study it
Increasing the residence time to 20 min provided little gain in was determined that 82% of the proline was consumed
yield, while reducing the residence time to 10 min afforded only (823.1 mg out of 1 g) (Figure 4).
Figure 4: The long-term stability of a proline packed bed in the α-aminoxylation reaction of hexanal. A solution of hexanal (3 M in EtOAc) and thiourea
3b (0.047 M in EtOAc) was passed through a packed-bed of proline (entering at the bottom of the column and exiting at the top) at 0 °C combined
with a solution of nitrosobenzene (1 M in EtOAc) in a coil at 5 °C with a 20 min residence time in the coil, for over 4 h. A) 20 mL of product was period-
ically collected into vials, reduced in batch, and purified. The resulting yields and enantioselectivities were plotted as a function of time. B) Close up
images of the proline column (see Figure 2A) showing the amount of proline consumed during the course of the reaction.
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As further support that the direct use of solid catalysts in flow is the amount of catalyst entering the system. In this particular
a viable strategy, two additional substrates, 3-phenylpropional- case, we predicted that, unlike 3-phenylpropionaldehyde, the
dehyde and isovaleraldehyde, were selected because they have isovaleraldehyde would form the oxazolidinone slowly.
different properties compared to hexanal, and thus we predicted Furthermore, we predicted that raising the packed-bed tempera-
that they would require alterations to the system to maximize ture would increase the rate of proline/isovaleraldehyde reac-
yield. As a starting point, the conditions optimized for hexanal tion resulting in more rapid formation of the soluble catalyst
were investigated. With 3-phenylpropionaldehyde, the use of a species. A quick survey of temperatures revealed that a 40 °C
0
°C column temperature, 5 °C coil temperature and a 20 min packed-bed temperature and a 20 °C coil temperature with a 25
coil residence time led to rapid reaction (based upon color min residence time provided 76% yield and 97% ee (Scheme 3).
change in the coil) and subsequent reactor clogging. This led us It is apparent from these results and our initial conditions that
to conclude that this aldehyde reacts rapidly with proline to substrate-to-substrate optimization can be rapidly achieved by a
yield an oxazolidinone with lower solubility than hexanal and quick survey of the three critical parameters. The data further
that lowering the overall residence time would limit the amount highlight the value of running reactions continuously.
of aldehyde reacting with proline. We confirmed that our asser-
tion was reasonable by reducing the residence time to 10 min to Conclusion
provide the product in 76% yield and 99% ee (Scheme 2).
We have demonstrated that a packed-bed of proline can be used
to continuously form a soluble catalyst through reaction with an
When isovaleraldehyde was investigated under the optimized aldehyde and cocatalytic urea. The formed soluble catalyst can
hexanal conditions, i.e., 0 °C column temperature, 5 °C coil support a variety of α-aminoxylation reactions with good yields
temperature and a 20 min coil residence time, there was little and high enantioselectivities. The system is designed so that the
conversion as judged by GC analysis. We were not surprised by first step involves the flow of aldehyde and urea solution
this observation, because increased steric hindrance about the through the proline packed-bed to generate the catalytic inter-
aldehyde can suppress the rate of oxazolidinone formation. mediate (presumably an oxazolidinone). This catalyst solution
With limited proline (in the form of oxazolidinone) entering the is then combined with a stream of nitrosobenenze, resulting in
system, the rate of α-aminoxylation decreases significantly. the α-aminoxylation. The most critical parameters that control
From our hexanal and 3-phenylpropionaldehyde experiments, the yield and selectivity were identified, and these parameters
we learned that by adjusting one of three parameters (residence were varied in order to optimize the system for each substrate.
time or the coil or packed-bed temperature) we could improve We predict that this basic setup can be adapted to generate a
Scheme 2: Reaction with 3-phenylpropionaldehyde through reactor setup.
aIsolated yield, due to the instability of the aldehyde, the product was reduced in batch to the corresponding 2-aminoxy alcohol prior to isolation.
bDetermined by chiral HPLC.
Scheme 3: Reaction with isovaleraldehyde through reactor setup.
aIsolated yield, due to the instability of the aldehyde, the product was reduced in batch to the corresponding 2-aminooxy alcohol prior to isolation.
bDetermined by chiral HPLC.
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Beilstein J. Org. Chem. 2011, 7, 1671–1679.
1
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