Translating the Enantioselective Michael Reaction to a Continuous Flow Paradigm with an Immobilized, Fluorinated Organocatalyst

Article abstract of DOI:10.1021/acscatal.5b01746

A novel polymer-supported fluorinated organocatalyst has been prepared and benchmarked in the enantioselective Michael addition of aldehydes to nitroalkenes. The system has proven to be highly efficient and displays excellent selectivities (er and dr) wit

Full text of DOI:10.1021/acscatal.5b01746

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Article
Translating the Enantioselective Michael Reaction to a Continuous
Flow Paradigm with an Immobilized, Fluorinated Organocatalyst
Irina Sagamanova, Carles Rodríguez-Escrich, István Gábor
Molnár, Sonia Sayalero, Ryan Gilmour, and Miquel A. Pericàs
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01746 • Publication Date (Web): 14 Sep 2015
Downloaded from http://pubs.acs.org on September 15, 2015
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Translating the Enantioselective Michael
Reaction to a Continuous Flow Paradigm with an
Immobilized, Fluorinated Organocatalyst
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Irina Sagamanova,a Carles Rodríguez-Escrich,a István Gábor Molnár,c Sonia Sayalero,a Ryan
Gilmourc,d* and Miquel A. Pericàsa,b*
a) Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona
(Spain).
b) Departament de Química Orgànica, Universitat de Barcelona, 08080 Barcelona (Spain).
c) Institut für Organische Chemie, Westfälische WilhelmsꢀUniversität Münster, Corrensstrasse
40, 48149 Münster (Germany).
d) Excellence Cluster EXC 1003 “Cells in Motion”. Westfälische WilhelmsꢀUniversität Münster,
Münster (Germany).
ABSTRACT: A novel polymerꢀsupported fluorinated organocatalyst has been prepared and
benchmarked in the enantioselective Michael addition of aldehydes to nitroalkenes. The system
has proven to be highly efficient and displays excellent selectivities (er and dr) with a wide
variety of substrates. Detailed deactivation studies have given valuable insights thus allowing the
lifespan of this immobilized aminocatalyst to be significantly extended. These data have
facilitated the implementation of enantioselective, continuous flow processes allowing either the
multigram synthesis of a single Michael adduct over a 13 h period, or the sequential generation
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of a library of enantiopure Michael adducts from different combinations of substrates (13
examples, 16 runs, 18.5 h total operation). A customized inꢀline aqueous workꢀup, followed by
liquidꢀliquid separation in flow, allows for product isolation without the need of chromatography
or other separation techniques.
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KEYWORDS: fluorinated organocatalyst • continuous flow • polystyreneꢀsupported catalysts •
enantioselective catalysis • Michael reaction
1. INTRODUCTION
Sustainability concerns have resulted in a change of paradigm where not only cost reduction,
but also waste minimization and catalyst recovery are crucial issues in process design. In this
context, continuous flow chemistry is one of the technologies expected to facilitate process
intensification, reducing the footprint of chemical plants whilst increasing their productivity,
modularity and flexibility.1 Despite the potential of immobilized catalysts for enantioselective
flow processes, the fine chemical industry still shows some reluctance to apply these techniques
due to the often limited lifespan of the reference homogeneous species. Designing more stable
homogeneous catalysts and successfully translating their corresponding batch processes to an
immobilized platform is therefore essential to further validate the potential of this approach.
Consequently, the preparation of supported catalysts with high activity and improved stability
holds great potential for both the industrial and academic chemical communities.
Since the pioneering reports by List, Lerner, Barbas2 and MacMillan3 laid the foundations of
modern organocatalysis, efforts to develop effective metalꢀfree small molecule catalysts have
intensified.4 One of the most successful organocatalysts is the diarylprolinol trimethylsilyl ether,
commonly known as the JørgensenꢀHayashi catalyst.5 Given the versatility of this species,
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which is able to exploit both the enamine and iminium ion activation mode, several groups have
tried to harness its potential by developing immobilized analogues.6 With the aim of enhancing
the sustainability profile of this catalyst, this laboratory has reported the preparation of a set of
solidꢀsupported derivatives7 whose robustness was established through recycling and
implementation of enantioselective continuous flow processes.8 These studies revealed that the
reusability of the catalyst was often compromised by the lability of the trimethylsilyl ether; this
has also been investigated spectroscopically in the homogeneous paradigm.9 Several approaches
have been employed to address this issue. First, it was demonstrated that reꢀsilylation is indeed
possible,77a although this has obvious drawbacks from an operational point of view and it
precludes continuous flow applications. The analogous methyl ether10 (rather than silyl) was also
prepared, but the polymerꢀsupported version proved to be less active and selective than the
parent system.77b Whilst catalysts with bulkier silyl ethers display increased stability,77d,e
significant structural changes can compromise reactivity and they tend to deactivate over time.
With these data in hand, efforts to immobilize the fluorinated compound 1,11 were initiated; this
system was introduced in asymmetric organocatalysis by Gilmour et al. in 2009.12 The
pyrrolidine derivative, designed to validate the gaucheꢀeffect hypothesis for molecular preꢀ
organization,13 has proven to be highly effective in the enantioselective epoxidations1212a,14 and
aziridinations15 of enals with great success, outperforming the JørgensenꢀHayashi catalyst in
some cases.16 Moreover, the low steric demand of the fluorine substituent, coupled with the
reactively inert CꢀF bond, ensures that any concerns regarding stability of this site are mitigated.
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Formatte
Superscrip
Formatte
Superscrip
Formatte
Formatte
It was therefore envisaged that compound 2, a polymerꢀsupported analog of 1, would display
increased robustness when compared to the structurally related silyl ethers. In addition, since the
active site of 1 (the pyrrolidine moiety) is not involved in the polymerization of 3 and the
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pyrrolidine moiety can freely rotate in polymer 2, we anticipated that the performance of 1 would
be preserved in the polymer. To test the validity of this hypothesis, compound 2 was prepared by
coꢀpolymerization of the divinylated derivative 3 with styrene (Scheme 1).
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Scheme 1. Strategy for the preparation of a polymerꢀsupported analog of 1.
2. RESULTS AND DISCUSSION
The synthesis of the target catalyst (Scheme 2) started with the addition of 4ꢀvinylphenyl
magnesium bromide (prepared in situ) to the proline derivative 4,17 which furnished 5 in 87%
yield.18 The Boc group was then cleaved in basic media, presumably via the corresponding
oxazolidinone, to generate amino alcohol 6.19 Deoxyfluorination of this amino alcohol, achieved
by treatment with diethylaminosulfur trifluoride20 (DAST), provided 3 in a concise threeꢀstep
sequence and 68% overall yield. Immediate fluorination of compound 6 was essential to avoid
spontaneous selfꢀpolymerization.
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KOH
BrMg
COOMe
N
N
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DMSO/MeOH, 120 ºC
95%
THF
87%
Boc
OH
Boc
5
4
DAST
CH2Cl2
−5 ºC → rt
82%
N
N
H
H
OH
F
3
6
Scheme 2. Preparation of the monomer 3.
Polymer 2 was obtained by suspension polymerization of the chiral monomer 3 with styrene in
water, following a modification of the procedure reported by Itsuno for the related amino
alcohol21 (Scheme 3). Since the monomeric species has two vinyl units, a crossꢀlinking agent
(e.g. DVB) was not required. Up to 65% of the functional monomer was incorporated to the
polymer, giving rise to resin batches with functionalization levels ranging between 0.80ꢀ1.15
mmol g–1. This polymer was characterized by IR, elemental analysis and SEM (see Supporting
Information for details). Moreover, it was possible to confirm the presence of the fluorine
substituent at the surface of the catalyst by EDX analysis
To characterize the behavior of this polymer further, the swelling ability with different solvents
was determined in CH2Cl2, toluene and water. As expected for a polystyrene derivative, greater
swelling was observed in CH2Cl2 than in water, whereas toluene led to an average result (see
Supporting Information for details).
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Scheme 3. Preparation of resin 2 by coꢀpolymerization of 3.
To evaluate the catalytic activity and recyclability of this system, the wellꢀestablished catalytic
addition of aldehydes to nitroalkenes22 was selected as the benchmark reaction for this study. It is
worth mentioning that there are no reports of 1 acting as a catalyst for this reaction. Indeed, this
study constitutes the first report of its application in the enamine activation mode.
As a model substrate set, propanal and (E)ꢀβꢀnitrostyrene were selected. An initial screening of
the addition reaction catalyzed by 2 is summarized in Tables 1 and 2. Gratifyingly, the reaction
in CH2Cl2 without any additives was complete within 11 h and gave excellent stereoselectivities
(entry 1). Consistent with literature reports on the homogeneous reaction, the addition of organic
acids increased the reaction rate,23 while maintaining the high levels of enantioselectivity (entries
2ꢀ8). As illustrated in Table 1, relatively strong acids such as TFA proved detrimental (entry 2),
whilst several carboxylic acids were tested with good results. Finally, it was observed that 4ꢀ
nitrophenol (the weakest of the acids examined) as an additive2323a,d provided the desired product
with excellent levels of enantioselectivity (95% ee) within 1.5 h. Good levels of diastereocontrol
(up to 96:4 syn/anti) were observed throughout this optimization process.
Formatte
Table 1. Effect of additives for the addition of propanal to βꢀnitrostyrene.a
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entry
additive
pKa
t [h]
Conv.c
drc
eee [%]
in H2Ob
–
(yieldd)
100 (99)
1
2
3
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–
11
5
96:4
94
–
CF3COOH
0.52
3.27
3.37
3.37
4.20
4.887
7.15
14 (n.d.)
100 (97)
81 (n.d.)
81 (n.d.)
100 (98)
98 (n.d.)
100 (99)
67:33
93:7
2ꢀFC6H4COOH
(R)ꢀmandelic acid
(S)ꢀmandelic acid
PhCOOH
3.5
5
95
94
94
94
94
95
85:15
83:17
95:5
5
3.5
4
CH3CH2COOH
4ꢀnitrophenol
96:4
1.5
95:5
aGeneral conditions: (E)ꢀβꢀnitrostyrene (22.4 mg, 0.15 mmol), propanal (33 ꢁL, 0.45 mmol),
catalyst 2 (10 mol%), additive (10 mol%) in 300 ꢁL of CH2Cl2 at room temperature. bpKa values
taken from literature sources.24 cConversion (%) and diastereomeric ratio (dr) determined by 1H
NMR spectroscopy of the crude reaction mixture. Isolated yield. Determined by chiral HPLC
analysis using a Chiralpak IC column.
d
e
The organocatalytic Michael addition reaction was then optimized in batch mode using catalyst
1 to provide a data set for comparison with the immobilized system (Table 2). The initial
reaction in CH2Cl2 reached completion in only 1 h furnishing the desired product 9aa in
quantitative yield and with excellent levels of both diastereoꢀ and enantioselectivity (dr 97:3
syn/anti and ee 97%. Table 2, entry 1). Indeed, the selectivity of the transformation was
essentially unaffected by changes in reaction medium (entries 4ꢀ7), and temperature variations
(entries 2 and 3).
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Table 2. The organocatalytic Michael addition in batch mode.a
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O
Ph
O
1 (x mol%)
NO2
NO2
+
Ph
4-nitrophenol
solvent, temperature
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Me
9aa
Me
7a
8a
(1 equiv.)
(3 equiv.)
conv.b
eed
[%]
catalyst/
additive
(mol%)
entry
solvent
t [h]
(yieldc)
[%]
drb
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CH2Cl2
CH2Cl2
CH2Cl2
1
>99 (99)
>99 (98)
>99 (97)
>99 (98)
>99 (95)
>99 (97)
93(86)
96:4
97:3
84:16
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94:6
94:6
96:4
96:4
95
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97
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95
e
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0.5
1
CH2Cl2 (dry)g
Toluene
EtOAc
2.5
16
24
1.5
8
THF
CH2Cl2
Toluene
>99 (98)
>99 (95)
5
aGeneral conditions: (E)ꢀβꢀnitrostyrene (22.4 mg, 0.15 mmol), propanal (33
µl, 0.45 mmol), catalyst 1 and 4ꢀnitrophenol in 300 µl of solvent at room
b
1
temperature. Conversion (%) and diastereomeric ratio (dr) determined by H
NMR spectroscopy of the crude reaction mixture. cIsolated yield (%).
dDetermined by chiral HPLC analysis. Reaction temperature: 0 °C. Reaction
e
f
temperature: 40 °C. gDry solvent, stored over 4 Å molecular sieves.
Next, the influence of reaction medium on the organocatalytic Michael reaction with resin 2 was
examined using several solvents whilst retaining 4ꢀnitrophenol as an additive. In all cases,
excellent diastereoꢀ and enantioselectivities were recorded (up to 95:5 and 96%, respectively; see
Table 3). Of the organic solvents investigated, CH2Cl2 proved to be beneficial in terms of
reaction rate, leading to full conversions in less than 1.5 h (Table 3, entry 1). Use of toluene also
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led to efficient reactions (5 h, entry 2), whereas EtOAc and THF resulted in more sluggish
processes (entries 3 and 4). To our delight, the reaction worked well in water (entry 5), affording
the desired compound in only 1.5 h and with enantioselectivities that were comparable to those
in CH2Cl2, irrespective of the low swelling ability of 2 in this solvent. Finally, lowering the
catalyst loading to only 5 mol% was well tolerated, and the reaction reached completion in 5 h
(entry 6).
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Table 3. Examining the effect of solvent on the addition of propanal to βꢀnitrostyrene in the
presence of 4ꢀnitrophenol and catalyst 2.a
O
Ph
O
2 (10 mol%)
NO2
NO2
+
Ph
4-nitrophenol (10 mol%)
solvent, rt
Me
Me
7a
8a
9aa
(3 equiv.)
(1 equiv.)
entry solvent
t [h]
Conv.b
(yieldc)
dr b
eed
[%]
1
2
3
4
5
6
CH2Cl2 1.5
100 (99)
100 (98)
99 (n.d.)
65 (n.d.)
100 (99)
100 (98)
95:5
95:5
95:5
93:7
95:5
95:5
95
96
93
92
95
95
Toluene
EtOAc
THF
5
16
16
1.5
5
H2O
e
CH2Cl2
aGeneral conditions: (E)ꢀβꢀnitrostyrene (22.4 mg, 0.15 mmol), propanal (33 ꢁL, 0.45 mmol),
catalyst 2 (10 mol%), 4ꢀnitrophenol (10 mol%) in 300 ꢁL of solvent at room temperature.
bConversion (%) and diastereomeric ratio (dr) determined by 1H NMR spectroscopy of the crude
c
d
reaction mixture. Isolated yield. Determined by chiral HPLC analysis using a Chiralpak IC
column. e5 mol% of catalyst 2 and 5 mol% of 4ꢀnitrophenol were used.
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An important conclusion of these studies is that immobilization of 1 (in polymer 2) does not
lead to any decrease in catalytic performance under the optimized set of reaction conditions. This
being secured, the scope of the reaction was next studied. Initially, variation of the donor quickly
revealed that a wide variety of aldehydes reacted smoothly with βꢀnitrostyrene (Scheme 4). This
result sharply contrasts with a similar catalytic resin previously prepared in our group,77a which
was extremely selective in the case of propanal.25 Using catalyst 2, linear aldehydes bearing
longer alkyl chains gave rise to the corresponding Michael adducts in short reaction times with
excellent enantioselectivities (9aaꢀ9fa). In the case of 3ꢀphenylpropionaldehyde, longer reaction
times were required to drive the reaction to completion (9ga).
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Formatte
O
O
Ph
2 (10 mol%)
NO2
NO2
+
Ph
4-nitrophenol (10 mol%)
CH2Cl2, rt
R
R
O
7a-h
(3 equiv.)
8a
9
(1 equiv.)
O
Ph
O
Ph
O
Ph
Ph
NO2
NO2
NO2
NO2
Me
9aa
9ba
9ca
9da
3.5 h, 96%b
96:4 dr,c 97% eed
1.5 h, 99%b
1.5 h, 97%b
1.5 h, 97%b
95:5 dr,c 95% eed
94:6 dr,c 97% eed
94:6 dr,c 97% eed
O
Ph
O
Ph
O
Ph
NO2
NO2
NO2
n-C10H21
6
Ph
9ea
9fa
9ga
3.25 h, 93%b
4 h, 95%b
6 h, 95%b
94:6 dr,c 97% eed
96:4 dr,c 97% eed
94:6 dr,c 94% eed
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Scheme 4. Scope of the aldehyde reaction partner.a
3
4
5
6
7
8
9
aGeneral conditions: (E)ꢀβꢀnitrostyrene (22.4 mg, 0.15 mmol), aldehyde (0.45 mmol), catalyst
2 (10 mol%), 4ꢀnitrophenol (10 mol%) in 300 ꢁL of CH2Cl2 at room temperature. bIsolated yield
(%). Diastereomeric ratio (dr) determined by H NMR spectroscopy of the crude reaction
mixture. dDetermined by chiral HPLC analysis.
c
1
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Variation of the nitroalkene partner was then investigated (Scheme 5). It was generally noted
that using aromatic nitro olefins (9abꢀ9ag) led to short reaction times, regardless of the nature of
the substituents (< 2.5 h). Nitroalkenes with heterocyclic aromatic groups, such as the 2ꢀfuryl or
2ꢀthienyl systems proved to be excellent Michael acceptors for this reaction, providing the
desired compounds in 1 h (9ahꢀ9ai). Employing nitro olefins with an aliphatic side chain (adduct
9aj) led to longer reaction times (5.5 h), and whilst the dr slightly decreased, high
enantioselectivities were recorded (97%). The characteristically high yields obtained throughout
(95ꢀ99%) are due to the simplified isolation procedure, made possible by the immobilization of
the catalyst: filtration, washing with 0.1 M NaOH to remove the additive and evaporation
rendered the pure products. Michael adduct 9ag is the sole exception to this, where the phenolꢀ
containing product had to be further purified by flash chromatography on silica gel.
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O
O
R
2 (10 mol%)
NO2
NO2
+
R
4-nitrophenol (10 mol%)
CH2Cl2, rt
Me
Me
7a
(3 equiv.)
8b-j
(1 equiv.)
9
10
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Br
Br
O
O
O
Br
NO2
NO2
NO2
Me
Me
Me
9ab
1.25 h, 98%b
97:3 dr,c 96% eed
9ac
9ad
1.5 h, 98%b
1.5 h, 98%b
96:4 dr,c 94% eed
94:6 dr,c 94% eed
OH
OMe
O
O
O
O
O
NO2
NO2
NO2
Me
Me
Me
9ae
9af
9ag
2.25 h, >99%b
95:5 dr,c 95% eed
2.25 h, >99%b
95:5 dr,c 95% eed
1 h, 97%b
93:7 dr,c 96% eed
O
O
S
O
Ph
O
NO2
NO2
NO2
Me
Me
Me
9ah
1 h, 95%b
93:7 dr,c 95% eed
9ai
9aj
5.5 h, 97%b
85:15 dr,c 97% eed
1 h, >99%b
94:6 dr,c 93% eed
Scheme 5. Scope of the nitroalkene.a
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aGeneral conditions: nitroalkene (0.15 mmol), propanal (33 ꢁL, 0.45 mmol), catalyst 2 (10
3
4
5
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7
8
b
mol%), 4ꢀnitrophenol (10 mol%) in 300 ꢁL of CH2Cl2 at room temperature. Isolated yield (%).
1
cDiastereomeric ratio (dr) determined by H NMR spectroscopy of the crude reaction mixture.
dDetermined by chiral HPLC analysis (GC for 9ag).
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To further establish the scope and limitations of the present methodology, catalytic reactions of
more challenging substrates mediated by 2 were also examined (Scheme 6). To this end, we
started with the βꢀbranched donor isovaleraldehyde. Although the reaction proved to be sluggish,
full conversions resulting in the formation of 9ha were observed after 20 h using the standard
conditions (10 mol% 2, 10 mol% 4ꢀnitrophenol). Whereas doubling the amount of additive had a
remarkable effect on the reaction rate, the optimal results were obtained with 20 mol% catalyst
loading in the presence of 20 mol% benzoic acid. Isovaleraldehyde was also found to react
smoothly with both 2ꢀbromoꢀ and 4ꢀbromonitrostyrene. After fineꢀtuning the reaction conditions,
the desired products 9hb and 9hc were obtained in quantitative yield after simple extraction with
0.1 M NaOH or saturated NaHCO3 without additional purification. As for αꢀbranched aldehydes,
it was found that isobutyraldehyde can be employed as the Michael donor with nitrostyrene and
4ꢀbromonitrostyrene, giving rise to products 9ia and 9ib, respectively, which bear quaternary
centers. Despite the severe steric hindrance of the corresponding trisubstituted enamine, full
conversions were achieved after 28 h using 30 mol% catalyst and 60 mol% of 4ꢀnitrophenol.
Extraction with 0.1 M NaOH gave the Michael adducts in good yields, but with moderate
enantioselectivities (66 and 72% ee, respectively). Unfortunately, trisubstituted nitroalkenes such
as αꢀmethylnitrostyrene or βꢀethoxycarbonylnitrostyrene proved unreactive, even after 42 h with
20 mol% catalyst and 4ꢀnitrophenol.
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O
Ph
9ha (Cond. A)
20 h, 96%b
95:5 dr,c 98% eed
9ha (Cond. B)
13 h, 97%b
93:7 dr,c 98% eed
9ha (Cond. C)
11 h, 96%b
97:3 dr,c >99% eed
5
6
7
8
NO2
9
Br
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Br
O
O
Br
O
O
NO2
NO2
NO2
NO2
9hb (Cond. A)
9hc (Cond. A)
11.5 h, 96%b
98:2 dr,c >99% eed
9ia (Cond. D)
28 h, >99%b
66% eed
9ib (Cond. D)
28 h, 93%b
72% eed
13 h, >99%b
95:5 dr,c 99% eed
Scheme 6. Scope of αꢀ and βꢀbranched aldehydes.a
aConditions A: nitroalkene (0.15 mmol), isovaleraldehyde (45 ꢁL, 0.45 mmol), catalyst 2 (10
mol%), 4ꢀnitrophenol (10 mol%) in 300 ꢁL of CH2Cl2 at room temperature. Conditions B: 20
mol% of 4ꢀnitrophenol. Conditions C: 20 mol% of 2 and 20 mol% PhCOOH. Conditions D (for
αꢀbranched aldehydes): nitroalkene (0.21 mmol), isobutyraldehyde (96 ꢁL, 1.05 mmol), catalyst
2 (30 mol%), 4ꢀnitrophenol (60 mol%) in 420 ꢁL of CH2Cl2 at room temperature. bIsolated yield
c
1
(%). Diastereomeric ratio (dr) determined by H NMR spectroscopy of the crude reaction
mixture. dDetermined by chiral HPLC analysis.
Having established the generality of the reaction, it was essential to demonstrate the stability of
the catalytic resin 2 upon reuse. To that end, a standard reaction was successively run in the
presence of 4ꢀnitrophenol and, after each cycle, the mixture was simply filtered off and washed
to remove all of the soluble materials. The remaining material 2 was then dried and used in the
subsequent cycle. The filtrate was extracted with 0.1 M NaOH, and provided pure compound
when full conversions were achieved. We were pleased to find that this polymer remained active
for at least eight runs (Table 4), although some progressive loss of activity was observed in the
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last cycles. Despite this, even in the eighth run the desired Michael adduct could be obtained in
68% isolated yield after 24 h. Importantly, the stereoselectivity remained constant throughout the
whole process.
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Table 4. Recycling experiments.a
O
Ph
O
2 (10 mol%)
NO2
NO2
+
Ph
4-nitrophenol (10 mol%)
CH2Cl2, rt
in all runs
dr > 95:5
95% ee
Me
Me
9aa
7a
8a
run
1
t [h]
1.5
2
Convb [%]
100
Yieldc [%]
99
98
97
98
97
83
97
68
2
100
3
2.5
4
100
4
100
5
6
100
6
12
24
24
84
7
100
8
70
aGeneral conditions: (E)ꢀβꢀnitrostyrene (41.0 mg, 0.275 mmol), propanal (60 ꢁL, 0.83 mmol),
catalyst 2 (10 mol%), additive (10 mol%) in 550 ꢁL of CH2Cl2 at room temperature. bConversion
1
(%) and diastereomeric ratio (dr) determined by H NMR spectroscopy of the crude reaction
mixture. cIsolated yield (%).
As outlined in the introduction, the major contributing factor to the deactivation of the
JørgensenꢀHayashi catalyst (i.e. desilylation) is no longer a risk owing to the installation of the
CꢀF unit. Consequently the slow decay observed in reaction efficiency can be attributed to
several factors, including mechanical degradation of the polymer or irreversible oxidation of
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reaction intermediates as demonstrated by Zlotin et al.26 Based on these precedents, a series of
recycling experiments were carried out under glovebox conditions to study the effect of oxygen
exclusion on catalyst stability. It was quickly noted that, after only a few reaction cycles in the
glovebox, the catalytic activity decreased. However, performing another run with the same
immobilized catalyst outside the glovebox immediately led to improved performance. This
suggests that the absence of water results in sluggish reactions. Three additional recycling
experiments were carried out to gain further insight into the factors responsible for catalyst
deactivation: performing the reaction under a nitrogen atmosphere (oxygen exclusion with 0.5
and 2.0 equivalents of water) and under air with 2.0 equivalents of water; in these experiments,
dry CH2Cl2 was used. The results indicate that trace amounts of water are beneficial for catalyst
turnover, whereas oxygen is detrimental (Table 5).
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Table 5. Recycling experiments in the presence of water.a
O
Ph
O
2 (10 mol%), H2O (x eq)
NO2
NO2
+
Ph
4-nitrophenol (10 mol%)
CH2Cl2, rt
in all runs
dr 96:4 or 95:5b
Me
Me
7a
8a
9aa 95% eec
Conv.b [%]
(under N2,
0.5 equiv. H2O)
100
Conv. b [%]
(under N2,
2.0 equiv. H2O) 2.0 equiv. H2O)
Conv. b [%]
(under air,
run
t [h]
1
2
3
1.5
2
100
93
89
80
94
79
96
2
81
aGeneral procedure: (E)ꢀβꢀnitrostyrene (41.0 mg, 0.275 mmol),
propanal (60 ꢁL, 0.83 mmol), catalyst 2 (10 mol%), additive (10
mol%) in 550 ꢁL of CH2Cl2 at room temperature. bConversion (%) and
1
diastereomeric ratio (dr) determined by H NMR spectroscopy of the
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crude reaction mixture. cDetermined by chiral HPLC analysis.
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These conditions that have allowed catalytic activity to be retained for longer periods of time
were then translated into a continuous flow process.27 An overview of the setꢀup used, where 500
mg of resin 2 were packed in a glass column (1 cm diameter), is shown in Figure 1.
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NO2
pump
NaO
0.1 M
pump
(aqueous phase)
NaOH
7, 8 and
4-nitrophenol
in CH2Cl2
T junction
coil
liq-liq
separator
packed bed reactor
3-way valve
pump
catalyst 2
back-pressure
regulator
organic
phase
CH2Cl2
O
R2
excess
aldehyde
(volatile)
NO2
+
N
H
F
R1
9
2
Figure 1. Continuous flow setꢀup.
Upstream of the column, two channels were connected to a threeꢀway valve that determined
which one would feed the catalytic column. Through the first channel dry, degassed CH2Cl2 was
passed through, its purpose being to swell the resin prior to the reaction and also to rinse any
remaining organic material from the column when the reagents have passed through. The second
channel was fed with a solution of 4ꢀbromonitrostyrene, propanal and 4ꢀnitrophenol in dry,
degassed CH2Cl2 with 2.0 equivalents of water.
Downstream, a backꢀpressure regulator was mounted to avoid bubble formation with volatile
solvents such as CH2Cl2, and then further a third pump with 0.1 M NaOH was assembled to
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allow for the aqueous workꢀup and removal of 4ꢀnitrophenol. The biphasic mixture was then
separated inꢀline using a Zaiput liquidꢀliquid separator, which gave rise to a yellow aqueous
phase (due to the presence of 4ꢀnitrophenolate) and an organic phase with the desired Michael
adduct and excess aldehyde (plus remaining nitrostyrene if the conversions were not complete).
In most cases simply evaporating the organic outstream furnished pure product where no further
purification was necessary.
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Using this setꢀup, full conversions were obtained during the first 10 h running the flow process at
100 µL min–1 (Figure 2). Over the following 3 h, a slight decrease in conversion was observed,
but remained above 97%. Overall, the desired Michael adduct was obtained in 95% yield and the
effective catalyst loading for the whole operation period was determined to be 1.6%; this
corresponds to an overall turnover number (TON) slightly above 60. The turnover frequency
(TOF) remained essentially constant at 4.6 hꢀ1 over the considered 13 h operation period.
Br
2 (500 mg,
f = 1.03 mmol g-1)
O
NO2
O
4-nitrophenol
(40 mol%)
+
+
NO2
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Me
9ab
8.87 g
7a
8b
(31.0 mmol, 95% yield)
dr 95:5, 96% ee
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Figure 2. Continuous flow process for polymerꢀsupported catalyst in the formation of 9ab.
The importance of correctly handling the packed catalyst columns is illustrated by the
following fact: when a still fully active column used in a flow experiment was dried, stored in
contact with the atmosphere and then attempted to recycle after reꢀswelling, it was found that
catalytic activity was lost to a high degree. This behavior can be easily understood when the
conditions of use of the catalytic column in flow are considered. Since an excess of aldehyde
reactant is employed, when flow is arrested most of the active sites in the column will be in the
active, enamine form. If the column is then dried and allowed to be in contact with air, oxidation
of the labile enamine units26 will lead to irreversible deactivation. As shown below, simply
keeping the catalytic column wet with dichloromethane when not in use efficiently suppresses
this problem.
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The possibility of using this continuous flow setꢀup to generate a library of compounds was
then explored. With a new batch of catalyst, a similar flow process was run with different reagent
combinations. Each pair of starting materials was circulated through the system for 30 min,
rinsing with solvent for 1 h afterwards. At the end of each day, and to avoid catalyst deactivation,
CH2Cl2 was passed at a rate of 25 ꢁl min–1 before continuing the flow experiments the next day.
Eight different combinations were run the first day and five more the second. On the third day
the first three examples were reꢀrun for 4 h each, thus demonstrating that the catalytic activity
was retained after several changes of substrates and an extended operation time. The compounds
synthesized and the results obtained during the generation of this library are summarized in
Figure 3. In total, 16 consecutive runs were carried out, with high yields and stereoselectivities
observed in all cases. Remarkably, the last run produced the desired Michael adduct in 90%
conversion, thus demonstrating the robustness of the catalyst. The overall TON for this set of
experiments was 72.
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Figure 3. Continuous flow process with polymerꢀsupported catalyst 2 applied to the preparation
of a compound library.
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To demonstrate the synthetic utility of the process, two different Michael adducts were further
derivatized to the corresponding 3,4ꢀdisubstituted pyrrolidines 10 by a oneꢀpot operation
involving reduction of the nitro group and reductive amination of the corresponding amino
aldehyde28 (Scheme 7). The process was carried out on a gram scale and the corresponding
products were transformed into the Nꢀtosylated derivatives 11 before determining the optical
purity. Excellent yields were obtained in both reactions for the two Michael adducts tested.
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Scheme 7. Derivatization of the adducts 9aa and 9ab to pyrrolidines 10.
3. CONCLUSIONS
In summary, an immobilized analog of the fluorinated aminocatalyst 1 has been developed and
showcased in a model transformation. Key to the success of this approach has been a polymer
design that does not affect the active site in 1 and, hence, maintains its catalytic performance.
The catalytic resin 2 shows great potential for the Michael addition of aldehydes to nitroalkenes
in batch and flow: this is the first example of this catalytic system in enamine activation. Catalyst
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deactivation studies have delineated the conditions responsible for degradation, thus allowing the
process to be streamlined to extend the lifespan of the catalyst. Applying this resin in a carefully
designed continuous flow setꢀup has allowed for the facile isolation of the desired Michael
adducts without chromatographic purification. This catalyst system has proved to be extremely
active, both in experiments that were run for extended periods of time and in the preparation of a
complex library of analogs. Importantly, the immobilized system shows comparable activity with
the batch process. This, together with the stability profile of this novel polymerꢀsupported
catalyst, is a powerful endorsement for the use of flow chemistry as an enabling synthesis
technology. Application of this catalytic resin to other synthetically valuable transformations is
in progress and will be reported in due course.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, compound and polymer characterization,
NMR spectra and HPLC chromatograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: mapericas@iciq.es
*Eꢀmail: ryan.gilmour@uniꢀmuenster.de
ACKNOWLEDGMENTS
Financial support from the Institute of Chemical Research of Catalonia (ICIQ) Foundation,
MINECO (grant CTQ2012–38594ꢀC02–01) and DEC Generalitat de Catalunya (Grant
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2014SGR827) is gratefully acknowledged. We also thank MINECO for support through Severo
Ochoa Excellence Accreditation 2014–2018 (SEVꢀ2013ꢀ0319). C.R.ꢀE. thanks the AGAUR
(Generalitat de Catalunya) for a Beatriu de Pinós B fellowship. R. G. and I. G. M. thank the
WWU Münster, and the Deutsche Forschungsgemeinschaft (SFB 858 and DFG EXC 1003
“Cells in Motion – Cluster of Excellence”, Münster) for generous financial support.
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L.; Wang, L.; Wang, W. D.; Zhang, Y.; Liu, C.; Wang, W. Chem. Eur. J. 2012, 18, 6718; g)
Keller, M.; Perrier, A.; Linhardt, R.; Travers, L.; Wittmann, S.; Caminade, A.ꢀM.; Majoral, J.ꢀP.;
Reiser, O.; Ouali, A. Adv. Synth. Catal. 2013, 355, 1748; h) Zheng, W.; Lu, C.; Yang, G.; Chen,
Z.; Nie, J. Catal. Commun. 2015, 62, 34.
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For recent reviews on asymmetric organocatalysis in continuous flow, see: a) Rodríguezꢀ
Escrich, C.; Pericàs, M. A. Eur. J. Org. Chem. 2015, 1173; b) Atodiresei, I.; Vila, C.; Rueping,
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b) Holland, M. C.; Gilmour, R. Angew. Chem. Int. Ed. 2015, 54, 3862.
10 For the homogeneous catalyst, see: Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253.
11 O’Hagan, D.; Royer, F.; Tavasli, M. Tetrahedron: Asymmetry 2000, 11, 2033.
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a) Sparr, C.; Schweizer, W. B.; Senn, H. M.; Gilmour, R. Angew. Chem. Int. Ed. 2009, 48,
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21 Itsuno, S.; Watanabe, K.; Koizumi, T.; Ito, K. React. Polym. 1995, 24, 219.
22
For the pioneering reports of organocatalytic asymmetric addition of aldehydes to
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For studies on the role of acidic additives and the general mechanism of diarylprolinol
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derivativesꢀcatalyzed Michael addition, see: a) PatoraꢀKomisarska, K.; Benohoud, M.; Ishikawa,
H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta 2011, 94, 719; b) Burés, J.; Armstrong, A.;
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D. G. J. Am. Chem. Soc. 2012, 134, 6741; d) Sahoo, G.; Rahaman, H.; Madarász, A.; Pápai, I.;
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24 Haynes, W. M. (Ed.), CRC Handbook of Chemistry and Physics, 95th ed., CRC Press/Taylor
and Francis Group: Boca Raton, FL, 2014ꢀ2015, section 5, pp 94ꢀ103.
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In that case (see ref. 7a), using a silylated diarylprolinol derivative, sterics were crucial for
the success of the reaction: propanal would react, but linear aldehydes with a longer chain turned
out to be much slower, whereas βꢀbranched substrates did not react at all.
26 Maltsev, O. V.; Chizhov, A. O.; Zlotin, S. G. Chem. Eur. J. 2011, 17, 6109.
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For some examples on the use of solidꢀsupported catalysts in continuousꢀflow Michael
addition of aldehydes to nitroalkenes, see: a) Ötvös, S. B.; Mándity, I. M.; Fülöp, F.
ChemSusChem 2012, 5, 266; b) Arakawa, Y.; Wennemers, H. ChemSusChem 2013, 6, 242; c)
Porta, R.; Benaglia, M.; Coccia, F.; Cozzi, F.; Puglisi, A.; Adv. Synth. Catal. 2015, 357, 377.
28 Kano, T.; Sigimoto, H.; Tokuda, O.; Maruoka, K. Chem. Commun. 2013, 49, 7028.
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A polystyreneꢀsupported fluorinated organocatalyst has been prepared by coꢀpolymerization and
showcased in the asymmetric Michael addition of aldehydes to nitroalkenes. High catalytic
activity and enantioselectivity were observed throughout. This immobilized aminocatalyst has
been implemented in a continuous flow design employed in the generation of a compound
library.
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