A polystyrene-supported 9-amino(9-deoxy)epi quinine derivative for continuous flow asymmetric Michael reactions

Article abstract of DOI:10.1039/c5ob00325c

A polystyrene (PS)-supported 9-amino(9-deoxy)epi quinine derivative catalyzes Michael reactions affording excellent levels of conversion and enantioselectivity using different nucleophiles and structurally diverse enones. The highly recyclable, immobilized catalyst has been used to implement a single-pass, continuous flow process (residence time: 40 min) that can be operated for 21 hours without significant decrease in conversion and with improved enantioselectivity with respect to batch operation. The flow process has also been used for the sequential preparation of a small library of enantioenriched Michael adducts.

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A Polystyrene-Supported 9-amino(9-deoxy)epi
Quinine Derivative for Continuous Flow Asymmetric
Michael Reactions
Javier Izquierdo,a Carles Ayats,a Andrea H. Henseler,a Miquel A. Pericàs* a,b
Cite this: DOI: 10.1039/x0xx00000x
A polystyrene (PS)-supported 9-amino(9-deoxy)epi quinine derivative catalyzes Michael reactions
affording excellent levels of conversion and enantioselectivity using different nucleophiles and
structurally diverse enones. The highly recyclable, immobilized catalyst has been used to implement a
single-pass, continuous flow process (residence time: 40 min) that can be operated for 21 hours
without significant decrease in conversion and with improved enantioselectivity with respect to batch
operation. The flow process has also been used for the sequential preparation of a small library of
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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enantioenriched Michael adducts
.
prepared using thiol-ene chemistry, has been briefly evaluated
in asymmetric organocatalysis.9
In any case, the application of immobilized cinchone
derivatives to asymmetric aminocatalysis in flow remains
completely unexplored.10
Introduction
In response to economy and sustainability concerns, the
chemical and pharmaceutical industries are paying increasing
attention to aspects such as process intensification, waste
reduction, and recycling of solvents and catalysts. Continuous
flow processing, still largely overlooked by the fine chemicals
and pharmaceutical sectors, satisfies many of these industrial
Results and discussion
requirements and is hence becoming an interesting alternative At the light of the excellent performance depicted by
to inherently less efficient batch processing.1 When catalytic organocatalysts immobilized onto resins through copper-
flow processes for the production of enantiopure materials are catalyzed alkyne-azide cycloaddition (CuAAC) reactions,11 we
considered, the use of immobilized catalysts2 appears as the considered the possibility of using this methodology for the
most promising alternative. Organocatalysts, not requiring immobilization of cinchona alkaloids. We report in this
metal cofactors and thus delivering reaction products devoid of communication the implementation of this strategy and the use
toxic metal impurities are perfect candidates for this task.
of the resulting functional resins as highly active and
The cinchona alkaloids have been known for over 200 years enantioselective organocatalysts for a variety of asymmetric
and have been used in multiple applications.3 In particular, the Michael additions under batch and flow conditions.
dense functionality of the molecules of these alkaloids has
Key to our plans, the vinyl group of the natural cinchona
allowed their easy conversion into versatile organocatalysts. alkaloids in the starting materials had to be converted to an
Primary amines prepared in this way, like the 9-amino(9- ethynyl group.12 With the ethynyl derivatives in hand, CuAAC
deoxy)epi cinchona alkaloids, have broadened the scope of reactions with azidomethyl polystyrene led uneventfully to
classical aminocatalysis, traditionally centered on secondary polystyrene-supported 9-amino(9-deoxy)epi cinchona alkaloids
amines such as proline and diarylprolinols.4
1a-4a with high levels of functionalization (from 0.87 to 0.91
C
inchona alkaloids and derivatives have been immobilized mmol/g. See ESI†). For comparison purposes the homogeneous
onto different solid supports like mesoporous silica,5 Nylon,6 analogues 1b-4b, resulting from CuAAC reactions with benzyl
magnetic nanoparticles,7 or organic polymers.8 However, only azide, were also prepared (Scheme 1).
a small family of polymer-supported cinchone derivatives,
The asymmetric Michael addition is one of the most
extended and general methods of C-C bond formation leading
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to the creation of stereogenic centers.13 Among the different (entry 5), probably because of inefficient swelling of the resin
strategies for achieving stereocontrol of this process, iminium in these solvents. The nature of the acidic co-catalyst required
activation of α,β-unsaturated carbonyl compound has provided for the reaction was also analyzed. CSA or p-TSA were
excellent results.13c-h The Michael addition of ethyl nitroacetate ineffective, the formation of reaction product being not
(
6a) to (E)–4–phenylbut-3-en-2-one (5a) was tested with observed at all (entry 7). The use of TFA led to partial
benchmark catalysts 1a-4a, as the densely functionalized conversion and decreased enantioselectivities (entry 8) and 2-
products arising from this reaction have found application in fluorobenzoic acid did not led to any significant improvement
synthesis.14
compared to benzoic acid (entry 9). Finally, parameters as
concentration or temperature were also modified. Increasing or
decreasing the 1M initial concentration led to lower
conversions and enantioselectivities (entries 11 and 12).
Somewhat surprisingly, by slightly increasing the temperature
to 30 ºC, we could achieve almost full conversion in the
standard reaction time (5 h) together with a small increase of
enantioselectivity (entry 13). Low-power microwave (MW)
irradiation (2 W) was attempted in order to increase the rate of
the transformation (entry 14), but without positive effect.
Table 1. Optimization of the reaction conditions.
Scheme 1: Synthesis of PS-supported 9-amino(9-deoxy)epi
cinchona alkaloids and their homogeneous analogues.
Among the PS-supported cinchona derivatives 1a-4a
,
quinine derivative 1a, gave the highest enantioselectivity. aConversion was determined by 1H NMR spectroscopy. bEnantiomeric
excess was determined by chiral HPLC analysis. cReaction set up in the
Likewise, the homogeneous quinine derivative 1b also showed
glovebox. dReaction concentration was 0.5 M. eReaction concentration was 2
the best performance in terms of enantioselectivity, with results
comparable to those obtained with resin 1a (See ESI†). We
accordingly focused on the optimization of reaction conditions
using the heterogeneous quinine derivative 1a as the catalyst.
We started the optimization screening solvents with different
characteristics. In the initial screening, CH2Cl2 showed the
highest levels of conversion and enantioselectivity (Table 1.
entry 2). A polar solvent mixture, such as a H2O/DMF (50:50)
mixture (entry 3), or THF (entry 6) afforded lower selectivities
and conversions. Moreover, the reaction did not proceed under
neat conditions (entry 1), in xylenes (entry 4) or in MTBE
M. fReaction heated to 30 ºC in a sand bath for 4h. gReaction under
microwave irradiation (2 W).
In spite of the excellent levels of enantioselectivity achieved
in the reaction, no appreciable levels of diastereoselectivity
were recorded in agreement with previous studies.14 It has to be
noted, however, that the γ-stereocenter is usually destroyed in
subsequent denitration or decarboxlation steps, the
stereochemistry at this point being thus irrelevant.14b,c, 15
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Table 2. Michael Addition of Ethyl Nitroacetate to Different Enones.
a Isolated yield; diastereomeric ratio and enantioselectivities of each diastereoisomer. bCyclopentenone (2 equiv.) and ethyl nitroacetate (1 equiv.) were used in
this experiment.
as substrates with extended conjugation that experience
regioselective addition to the β position (7m). 4-Alkyl
substituents
(
7n and 7o
)
are also suitable for this
transformation, the corresponding additions taking place with
excellent enantioselectivity. In the same manner, 1-aryl-1-
penten-3-one substrates (7s) undergo highly enantioselective
addition, but at decreased rate. To our delight, more
conformationally constrained systems like cyclic enones are
also optimal substrates (7q-r) under catalysis by 1a. Only 2-
cyclopentenone (7p) shows some limitations, the corresponding
addition taking place at slower rate and with lower
enantioselectivity.
Scheme 2: Decarboxylation and denitration of 7a leading to
suppression of the γ-stereocenter
Next, the applicability of 1a with different pronucleophiles
in the same reaction was tested (Table 3). Gratifyingly, a
variety of C-H acids underwent Michael addition to a broad
range of enones under slightly re-optimized reaction conditions.
Bromonitromethane afforded the target Michael adducts with
high yield and excellent enantioselectivity by simply increasing
Once the reaction conditions were optimized, the next step
was to explore the scope of the Michael addition of 6a to a
representative family of enones catalized by resin 1a (Table 2).
4-Aryl-substituted 3-buten-2-ones are optimal substrates,
irrespectively of the substitution pattern in the aryl group and
the electronic characteristics of its substituent
(7a-7k).
catalyst amount to 20 mol% and reaction time (8a-e).
Heteroaryl substituents, as furyl (7l), are well tolerated as well
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Malonitrile
(
9a
-
c), phenylsulfonylnitromethane
(
11
)
and performed. In six consecutive cycles performed at constant
Meldrum´s acid (12a-b), which had not been previously used in reaction time, no decrease in ee was observed. On the other
Michael additions mediated by cinchone-derived amines, were hand, a slight decrease in conversion between cycles was
also found to be suitable substrates when treated with an excess recorded (see ESI†).
of the enone. In a similar manner, β-keto acid 6d can be a
The high catalytic activity exhibited by 1a and its
valuable donor in additions mediated by 1a. The reaction takes robustness convert this catalytic resin into a suitable candidate
place with concomitant decarboxylation, leading to the 1,5- for a continuous flow processing. The very simple flow reactor
dicarbonyl compounds (10a
-c). As it can be observed in Table used to test this hypothesis involved 450 mg of resin 1 (f = 0.87
3, most of the structural types of enones explored in Table 2 are mmol.g-1) packed into a Teflon® tube (1/4 inch i.d.) between
also suitable for the addition of this broad family of C-H acids.
two plugs of glass wool. The catalytic reactor was heated to
30 ºC while a solution of the two reactants (5a and 6a) and
benzoic acid in CHCl3 (no reaction occurs in the absence of
catalyst) was pumped into the system at 50 μl/min (equivalent
to ≈ 40 min residence time) (see ESI†). Notably, 3.6 g (12.9
mmol) of 7a were collected in 21 hours of operation,
corresponding to a TON of 32 (Figure 1).
Table 3. Michael Addition of Different Nucleophiles to Enones.
Fig. 1. Continuous Flow Process.
Catalytic asymmetric flow processes based on immobilized
catalytic species are of particular interest since focused libraries
aimed at lead discovery and optimization can be very easily
prepared in this way using a single set-up operated in a
sequential manner.11a,d,16 Taking advantage of the versatility of
the PS-supported cinchona aminocatalyst 1a, a diverse library
of enantioenriched Michael adducts could be sequentially
prepared (Figure 2). Thus, using optimized flow conditions,
aConditions:
1 (20 mol%), PhCOOH (40 mol%), 5a (1 equiv.),
b
bromonitromethane (2 equiv.). 3 equiv. of β-ketoacid and 1 equiv. of enone
were used. cEnantiomeric excess was determined on the 1,4-dicarbonyl
compound derivative resulting from hydrolysis of the nitrosulfonyl moiety
(See ESI†).
five Michael adducts (7c, 7k, 11a, 12a, and 12b) were prepared
by combination of four different enones with three
nucleophiles. Each solution containing the enone, nucleophile
and the benzoic acid, was circulated through the system at
50 μl/min for 2h (first hour was utilized for stabilization of the
flow system whilst only the effluent corresponding to the
second hour was collected). For the avoidance of cross-
One of the most important advantages offered by
immobilized catalysts is the possibility to recover them by
simple filtration and reuse in a new catalytic cycle. To assess
the robustness of 1a, its recycling in the model Michael
addition of ethyl nitroacetate (6a) to the enone (5a) was
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contamination, the column was washed with CHCl3 for 1h
between the preparation of two consecutive adducts. The
complete process takes place with remarkable productivity
(TOF = 1.4-3.2 mmolproduct/mmolresin · h) and affords a library
of Michael adducts with increased enantioselectivity in
comparison to the corresponding batch processes (Tables 2
and 3).
Experimental
General procedure for the Michael addition of ethyl nitroacetate
to enones catalyzed by resin 1a.
Polymer-supported quinine derivative 1a (11.2 mg, 0.01 mmol, 10 mol%)
was added to a vial with a mixture of α,β-unsaturated ketone
5 (0.1 mmol,
1 equiv.), ethyl nitroacetate 6a (22 μL, 0.2 mmol, 2 equiv.) and benzoic
acid (2.4 mg, 0.02 mmol, 20 mol%) in CHCl3 (0.1 mL) and the mixture
was stirred at 30 ºC in a sand bath for 4 h. Then, the resin was filtered off,
washed with CHCl3 (3 x 1 mL) and dried under vacuum. The combined
liquid phases were concentrated under reduced pressure. The reaction
crude was directly purified through column chromatography eluting with
cyclohexane and (1- 20) % AcOEt.
Acknowledgements
This work was funded by MINECO (grant CTQ2012-38594-
C02-01), DEC (grant 2014SGR827), and ICIQ Foundation. We
thank MINECO for support through Severo Ochoa Excellence
Accreditation 2014−2018 (SEV-2013-0319). J. I. thanks ICIQ-
IPMP-2013 for a fellowship. C. A. thanks MICINN for a Juan
de la Cierva fellowship. A. H. H. thanks the MECD for an FPU
predoctoral fellowship.
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cinchona alkaloids immobilized onto polystyrene resins behave
as highly efficient organocatalysts promoting asymmetric
Michael additions under batch and flow conditions. Resin 1a
has shown high robustness and versatility for the activation of
enones towards the addition of C-nucleophiles. Moreover, the
suitability of the developed continuous flow process for the
sequential preparation of a small library of enantiopure adducts
has been demonstrated.
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