A Recyclable, Immobilized Analogue of Benzotetramisole for Catalytic Enantioselective Domino Michael Addition/Cyclization Reactions in Batch and Flow

Article abstract of DOI:10.1021/acscatal.5b02121

A polystyrene-supported, enantiopure benzotetramisole (BTM) analogue (5) has been synthesized from (2S,3S)-phenylglycidol through a five-step sequence involving a copper-catalyzed alkyne azide cycloaddition (CuAAC) reaction as the final, immobilization st

Full text of DOI:10.1021/acscatal.5b02121

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Article
A Recyclable, Immobilized Analogue of Benzotetramisole
for Catalytic Enantioselective Domino Michael
Addition/Cyclization Reactions in Batch and Flow
Javier Izquierdo, and Miquel A. Pericàs
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02121 • Publication Date (Web): 04 Dec 2015
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A Recyclable, Immobilized Analogue of Benzotetramisole
for Catalytic Enantioselective Domino Michael
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Addition/Cyclization Reactions in Batch and Flow
Javier Izquierdo,† Miquel A. Pericàs.*†‡
†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and
Technology, Avinguda Països Catalans 16, 43007 Tarragona, Spain.
‡Departament de Química Orgànica. Universitat de Barcelona (UB), 08028 Barcelona, Spain.
ABSTRACT: A polystyreneꢀsupported, enantiopure benzotetramisole (BTM) analogue (5) has
been synthesized from (2S,3S)ꢀphenylglycidol through a five steps sequence involving a copperꢀ
catalyzed alkyne azide cycloaddition (CuAAC) reaction as the final, immobilization step. The
functional resin 5 (f = 0.9 mmol gꢀ1) has been successfully used as a highly active and
enantioselective catalyst in the domino Michael addition/cyclization reaction of in situ activated
arylacetic acids (7) with chalconeꢀtype tosylimines (6) leading to dihydropyridinones 8 (17
examples) affording the products with excellent yields and very high enantioselectivity (mean ee =
97.4%). The deactivation of 5 by species present during the catalytic process has been studied, and
pivaloyl chloride (required for the activation of the arylacetic acid) has been identified as the main
source of deactivation. A simple experimental protocol taking this fact into account has allowed the
multiple recycling of 5 with only marginal decrease in catalytic activity and the implementation of a
continuous flow process where the activation of phenylacetic acid (residence time = 14.2 min), the
asymmetric domino Michael addition/cyclization reaction (residence time = 7.5 min), and aqueous
workꢀup are performed sequentially delivering the dihydropyridinone product as a clean
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dichloromethane solution [0.54 mmol catalyst sample; 11 h operation; 8a (4.44 g, >99.9% ee)]. The
supported catalyst 5 has also been used in a new domino Michael addition/cyclization reaction
involving saccharinꢀderived tosylimines 9 as electrophiles and leading to 8,9ꢀdihydroꢀ7Hꢀ
benzo[4,5]isothiazolo[2,3ꢀa]pyridinꢀ7ꢀoneꢀ5,5ꢀdioxides 10 (8 examples) in high isolated yields and
diastereoselectivities and excellent enantioselectivities (mean ee = 98%). A single sample of 5 (0.5
g, 0.45 mmol) has been used for the sequential preparation in batch of a library of 7 different
derivatives 10 at the gram scale (ca. 10 g, accumulated TON = 51), the whole process being
performed without any column chromatography purification. The increased diastereoselectivity
recorded with 5 in reactions involving sterically congested arylacetic acids (with respect to
homogeneous BTM) has been rationalized through the occurrence of steric interactions between the
sulfonylimine and the linker plus support catalyst fragments leading to additional destabilization of
the transition state leading to the minor, cis diastereomer of products 8/10.
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KEYWORDS: Asymmetric catalysis • Isothioureas • Polystyreneꢀsupported catalysts • Domino
reactions • Continuous flow.
1. INTRODUCTION
Organocatalysts present inherent practical advantages such as tolerance to moisture or oxygen,
high availability (as many organocatalysts are derived from abundant natural products), and low or
no toxicity. In addition, organocatalysis provide simple and effective pathways for transformations
hardly achievable by other methodologies.1 For all these reasons, organocatalysis is called to play
an increasingly important role in key industrial sectors, including the pharmaceutical industry.
When this new perspective is considered, aspects of organocatalysis such as reduced catalyst
loadings, easy recovery and the possibility of repeated recycling come to the front line not only for
sustainability, but also for economic reasons.
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The use of chiral immobilized catalysts by the synthetic community is experiencing a continued
increase due to the significant advantages provided by this strategy: straightforward catalyst
separation and recovery can be achieved by a simple filtration (polymer matrices) or magnetic
decantation (magnetic nanoparticles) with suppression of wasteful workꢀup stages. In addition,
sufficiently active immobilized catalytic systems allow the implementation of flow process for the
continuous production of chiral enantiopure compounds.2
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Enolate addition to a variety of electrophiles has become one of the most employed
methodologies for the formation of CꢀC bond.3 Thus, new methodologies for asymmetric enolate
generation are highly desirable. In this domain, methodologies involving the use of transition metal
catalysts have been documented for years,4 but Lewis baseꢀtype catalysts such as secondary
amines5, isothioureas6, cinchona alkaloid derivatives7 and Nꢀheterocyclic carbenes (NHCs),8 have
emerged as suitable precursors for the generation of chiral enolates under less demanding
experimental conditions. In particular, the generation of chiral ammonium enolates9 as highly
versatile organocatalytic intermediates has been successfully achieved by in situ activation of
carboxylic acids, avoiding the tedious task of isolation and purification of these intermediates.10
Within this area, benzotetramisole (BTM), an amidineꢀbased catalyst originally introduced by
Birman11 has been successfully employed as a nonꢀenzymatic acyl transfer isothiourea catalyst for
kinetic resolutions and desymmetrization processes.12 BTM was subsequently employed by Romo13
as a precursor of ammonium enolates in a high stereoselective intramolecular domino process
known as Nucleophile Catalyzed AldolꢀLactonization (NCAL), while Smith has expanded its use to
a variety of processes.14 To the best of our knowledge, the use of supported isothioureas as
organocatalysts has not been yet reported in the chemical literature.
Dihydropyridones and 1ꢀdihydroꢀ1Hꢀbenzothiazolopyridines are recognized structures which can
be found in cores of many biologically active natural products and drugs with widespread
pharmaceutical antitumoral and antibacterial activities.15 These motifs have been synthesized
traditionally through the azaꢀDielsꢀAlder reaction16 but there are few asymmetric methodologies to
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promote this transformation. While the first enantioselective methodology leading to these
substances was a metalꢀcatalyzed reaction developed by Carretero,17 several organocatalytic
approaches have been reported in the last years involving the JørgensenꢀHayashi catalyst,18 Nꢀ
heterocyclic carbenes,19 or isothioureas.14b, 14i
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Within our research program aiming at developing new immobilized catalysts with improved
characteristics over their homogeneous counterparts we considered that BTM, for its widespread
use, was an optimal candidate for immobilization. An analysis of the BTM structure (Figure 1)
suggested that position 3 could be ideal for immobilization purposes, since an additional substituent
at this carbon would occupy a spatially remote position with respect to the catalytic site (the
thiourea moiety). The retrosynthetic introduction of a functional carbon atom in this position
ultimately leads to phenylglycidol, a material readily available in enantiopure form at the multigram
scale by catalytic asymmetric Sharpless epoxidation,20,21 as the chiral edduct for the preparation of
the immobilized BTM analogue. Interestingly, this approach could be adapted for diversity and
fineꢀtuning, given the broad variety of arylglycidols available in enantiopure form by Sharpless
epoxidation.
Figure 1. Design and retrosynthetic analysis of BTM derivatives suitable for immobilization.
We wish to report the preparation according to this design of the PSꢀsupported BTM derivative 5,
involving the use of a copperꢀcatalyzed alkyne azide cycloaddition (CuAAC) reaction22 (click
chemistry23) as the tool for the immobilization of the properly functionalized intermediate 4 onto
azidomethyl polystyrene, and the use of 5 as a highly efficient organocatalyst for the domino
Michael addition/cyclization reactions of arylacetic acids with chalcone or saccharinꢀderived tosyl
imines.24
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2. RESULTS AND DISCUSSION
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The synthesis of the supported catalyst 5, started from enantiopure (>99.5% ee) alkynyl
epoxyether 125 which was regioselectively ringꢀopened with ammonia to afford amino alcohol
2.25a,26 Then, stoichiometric amounts of amino alcohol 2 and chlorobenzothiazole were heated in a
pressure tube to afford the propargylated benzothiazole 3, which contains all the structural elements
for isothiourea synthesis and immobilization. Cyclization to isothiourea 4 was achieved by a twoꢀ
step protocol involving mesylation of the secondary hydroxy group followed by intramolecular SN2
displacement by the nucleophilic benzothiazole nitrogen of compound 3. The absolute
configuration of compound 4 was confirmed by Xꢀray difraction.27 Finally, a CuAAC reaction with
azidomethyl polystyrene afforded the supported BTM analogue 5 with high immobilization yield
(98%; f = 0.9 mmol.gꢀ1) (Scheme 1). Full experimental details for the preparation of 5 are given in
the Supporting Information.
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Scheme 1. Synthesis of the PSꢀsupported BTM analogue 5.
As an initial assessment of the performance of the immobilized isothiourea 5, we decided to test it
as a catalyst in the synthesis of dihydropyridinones previously reported by Smith et al.14b (Table 1).
Following the reported protocol, phenylacetic acid 7a, iꢀPr2NEt and pivaloyl chloride (2 equivalents
each) were mixed together before addition to a mixture of tosylimine 6a and supportedꢀBTM 5,
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followed by a second addition of base. Gratifyingly, full conversion into dihydropyridinone 8a was
observed in only 2 hours, the product being obtained with excellent enantioselectivity (entry 1).
Modification of the activating reagent (entry 2), work at higher concentration (entry 3) or a decrease
in the amount of the anhydride precursors (entry 4) led to lower conversion. Greener solvents, such
as EtOAc (entry 5) or 2ꢀmethyltetrahydrofuran (2ꢀMeꢀTHF, entry 6), were also tested but
conversion drastically decreased in these media. From a practical perspective, we found that preꢀ
activation time was unnecessary for the efficient formation of the mixed anhydride, and that this
key intermediate could be formed efficiently in a oneꢀpot manner, with all the reagents added
simultaneously. This simplified procedure allowed reducing the reaction time to 2 hours and the
amount of base to only 2 equivalents (entry 7). The use of phenylacetyl chloride was also tested in
the reaction (entry 8), but this led to significantly lower conversion. Although very high
enantioselectivity was recorded under these conditions, the catalyst was deactivated after the
reaction (see Supporting Information). This observation led us to reꢀconsider the optimal amount of
pivaloyl chloride to be used in the reaction. After some experimentation, we found that reducing the
amount of this reagent to 1.75 equiv. was beneficial for preserving the catalytic activity of 5, and
this modification was adapted for future work under the conditions of entry 7. At this point, we
decided to compare the performance of 5 with that of unsubstituted benzotetramisole (BTM) in the
reaction of 6a with 7a under the previously optimized reaction conditions (entry 7, with 1.75 equiv.
of PivCl). As it can be seen (entry 9), catalyst 5 is clearly advantageous under these conditions,
leading to notably improved diastereoselectivity and isolated yield.
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Table 1. Optimization of the tandem Michael addition/cyclization reaction of phenylacetic acid 7a
and tosylimine 6a.
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Entry Modification of standard conditions
Conversiona eeb
Standard conditionsc
> 95%
62%
96%
1
TsCl instead of PivCl
ꢀ
2
3
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5
6
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8
9
CH2Cl2 (0.5 M) instead of CH2Cl2 (0.2 M)
1.2 equiv. of PivCl and BnCOOH
EtOAc instead of CH2Cl2
60%
ꢀ
ꢀ
47%
26%
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2ꢀMeꢀTHF instead of CH2Cl2
9%
ꢀ
2 equiv. of iꢀPr2NEt instead of 2.0 + 2.5 equiv.d
> 95%e
97%
99%
98%
BnCOCl instead of PivCl and BnCOOH
43%
As in entry 7,f but with BTM as the catalyst
74%g
b
c
aBy 1H NMR. By chiral HPLC. Phenylacetic acid 7a (2 equiv.) was preꢀactivated with pivaloyl
chloride and iꢀPr2NEt (2 equiv. each) and stirred at 0 ºC for 15 minutes before addition to a mixture
d
e
of PSꢀBTM 5 and tosylimine 6a. No preꢀactivation for phenylacetic acid 7a. 79% isolated yield
and >98:2 d.r. With 1.75 equiv of PivCl, isolated yield was 83%, with 98.5:1.5 d.r. and 99% ee.
f1.75 equiv. of PivCl. g68% isolated yield and 82:18 d.r.
The scope of the tandem Michael addition/cyclization reaction was explored by using diverse
arylacetic acids
7
or chalconeꢀderived tosylimines
6
(Table 2), the corresponding
dihydropyridinones 8a-q being obtained in excellent yield and enantioselectivity for the different
substituent types tested, as reported for BTM.14b Homogenous BTM has demonstrated to be
sensitive to orthoꢀsubstituted arylacetic acids, displaying low diastereoselectivity for this kind of
substrates. Interestingly, this limitation is completely suppressed with the immobilized BTM
analogue 5, which rendered the products featuring this substitution pattern in very good
diastereomeric ratio and isolated yields (8b and 8c). This behavior indicates that the substituent at
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Cꢀ3 on the BTM structure, introduced to allow immobilization, further destabilizes the transition
state leading to the minor cis diastereomer during the addition step (see Figure 3 below for a
pictorial representation of these destabilizing interactions in an analogous case). In contrast with our
results, another BTM derivative reported in the literature featuring a similar transꢀsubstitution
pattern demonstrated to be less active than unsubstituted BTM.28
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The reaction was also tested with carboxylic acids of other structural types. Not unexpectedly,
arylacetic acids with αꢀsubstitution or aliphatic carboxylic acids did not yield any product in the
reaction.29
Table 2. Domino Michael addition/cyclization of in situ activated arylacetic acids 7 with chalconeꢀ
derived tosylimines 6
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aFirst line: isolated yield after column chromatography; second line: diastereomeric ratio
determined by H NMR; third line: enantiomeric excess determined by chiral HPLC. Results
obtained with homogeneous BTM.14b
1
b
Once the high catalytic activity and the versatility of 5 in domino Michael addition/cyclization
reactions had been established, the robustness of the catalyst in this benchmark reaction was tested.
To this end, a study of the recyclability of the PSꢀsupported BTM analogue 5 was performed (Table
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3). The experiments were carried out by addition of the reagents and freshly distilled solvent to a
sample of 5. After 2 h, the reaction mixture was separated from the catalytic resin by simple
filtration, and the resin was washed with dichloromethane before reuse. Gratifyingly, catalyst 5
showed high activity in six consecutive cycles, no significant decrease of catalytic activity being
recorded. Noteworthy, the enantioselectivity of the process kept constant (97% ee) over the six
reaction cycles. To get further insight of the behavior of 5 during recycling, the kinetic profile of
two consecutive, identical experiments was followed by NMR. It could be established in this
manner that the reaction profiles are superimposable, thus discarding the possibility of deactivation
processes obscured by the use of excess catalyst (see Supporting Information).
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Table 3. Recycling of the PSꢀBTM analogue 5 in the domino Michael addition/cyclization reaction
of chalconeꢀderived tosylimine 6a and phenylacetic acid 7a.
NTs
Ph
Ph
a
O
Ts
Ph
Ph
6a (1 equiv.)
5 (10 mol%)
N
+
PivCl (1.75 equiv.),
i-Pr2NEt (2.0 equiv.)
CH2Cl2 (0.2 M),
Ph
Ph
CO2H
7a (2 equiv.)
8a
2 h, 0 ºC to r.t.
Cycle
Conversionb
87%
eec
97%
97%
97%
97%
97%
97%
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5
6
85%
87%
85%
83%
83%
aReactions performed at 0.15 mmol scale. bBy 1H NMR. cBy chiral HPLC.
Encouraged by these promising results of recyclability, the possibility of implementing a
continuous flow protocol comprising both processes; i. e., the preꢀactivation of the carboxylic acid
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reactant and the organocatalytic domino transformation, taking place sequentially in the same setꢀup
was envisaged. Although challenging in principle, a protocol with these characteristics would
realize all the simplification potential and practical advantages of the flow paradigm with respect to
classical batch processing for the considered transformation.
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The required flow setꢀup (Figure 2) is described in detail in the Supporting Information. The nonꢀ
catalytic formation of the mixed anhydride should take place in a simple tubular reactor with length
optimized for full conversion, and the mixed anhydride would then mix with the preꢀformed tosyl
imine at the entrance of a catalytic reactor containing a suitable amount of PSꢀsupported BTM
analogue 5. In line IR analysis at the reactor outlet should allow manipulation of the different flow
rates (mixed anhydride and tosylimine) for the achievement of the desired conversion level. As an
additional requirement, the amount of deactivating pivaloyl chloride entering in contact with the
catalytic resin should be minimized. In order to perform continuous product isolation, water would
be added at controlled flow rate to the reaction output (to allow extraction of pivalic acid and iꢀ
Pr2NEt), and phase separation would be performed inꢀline. For the implementation of the flow
process, resin 5 (600 mg, 0.54 mmol) was swollen with dichloromethane in the sizeꢀadjustable,
mediumꢀpressure chromatography column used as reactor, and dichloromethane solutions of
tosylimine 6a and the mixed phenylacetic pivalic anhydride were pumped into the column at a
combined flow rate of 110 ꢁl/min (residence time of 7.5 min). The mixed anhydride, in turn, was
prepared by combining dichloromethane solutions of iꢀPr2NEt/phenylacetic acid 7a and pivaloyl
chloride, and pumping the combined solution through a loop coil at a flow rate of 55 ꢁl/min,
corresponding to a residence time of 14.2 min residence time. Conversion of 6a into 8a was
continuously monitored by inꢀline FTIR, and the reaction mixture and quenched by continuous
addition of water at the reactor's outlet by means of another HPLC pump (flow rate = 120 ꢀL/min).
The integrated inꢀline liquidꢀliquid separator allowed the continuous collection of the
dichloromethane phase, from which 8a was obtained by simple evaporation. The system was
operated for 11 h with very high conversion and increased enantioselectivity (> 99.9% ee) in
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comparison with the batch process.24d The material converted during the whole flow experiment
represented a TON of 22.5 for the sample of immobilized catalyst used, and the amount of
recrystallized 8a obtained during the experiment was 4.44 g (70% yield). Further details can be
found in the Supporting Information.
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Figure 2. Continuous flow process setꢀup for the preparation of 8a.
SupportedꢀBTM 5 showed high activity also with cyclic sulphonylimines such as the sultams
derived from saccharin (9), and we reasoned that the tricyclic derivatives 10 resulting from the
domino Michael addition/cyclization reaction of these derivatives could present interest as drug
candidates. A concise screening of the reaction with these derivatives also revealed high tolerance
in the aryl substitution pattern for both substrate molecules, the reaction affording the 8,9ꢀdihydroꢀ
7Hꢀbenzo[4,5]isothiazolo[2,3ꢀa]pyridinꢀ7ꢀoneꢀ5,5ꢀdioxides 10 in excellent isolated yields, high
diastereoselectivities and excellent enantioselectivities (Table 4).
Table 4. Domino Michael addition/cyclization of in situ activated arylacetic acids 7 with different
saccharinꢀderived Michael acceptors 9
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aFirst line: isolated yield after column chromatography; second line: diastereomeric ratio
determined by 1H NMR; third line: enantiomeric excess determined by chiral HPLC.
Next, the high catalytic activity, robustness and recyclability of the supported BTM analogue 5 in
this transformation was further demonstrated by using in a repeated manner the same sample of the
immobilized catalyst for a series of experiments at the gram scale. Thus, to a 500 mg (0.45 mmol)
sample of resin 5 swollen in dichloromethane under argon at 0 ºC, were added sequentially an
arylacetic acid 7, the corresponding saccharineꢀderived Michael acceptor 9, dichloromethane, iꢀ
Pr2NEt, and pivaloyl chloride, and the domino Michael addition/cyclization reaction was allowed to
proceed to completion while the mixture warmed to room temperature. The reaction mixture was
decanted with a syringe, and the resin washed with freshly distilled dichloromethane before the
addition of a new combination of reactants. Up to seven different derivatives 10 were sequentially
prepared in this manner, the resin retaining most of its activity by the end of the last reaction cycle
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(Table 5). Almost 10 g (combined weight) of pure tricyclic derivatives 10 were isolated in these
experiments and the accumulated TON (for the employed catalyst sample) was 51. Worth to be
noted, the limited solubility of these products, which prevents the implementation of efficient flow
processes for their preparation, allows its easy purification by simple crystallization. No column
chromatography was used at all during the purification process.
9
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Table 5. Sequential preparation at the gram scale of a library of tricyclic derivatives 10 by domino
Michael addition/cyclization of inꢀsitu activated arylacetic acids 7 with different saccharineꢀderived
Michael acceptors 9.
Reaction
Product
Yield
eec
[%]
Run
Ar1
Ar2
d.r.b
time [h] (weight [g]) [%]a
Ph
Ph
Ph
1ꢀnaphthyl
pꢀchlorophenyl
Ph
2
2
2
2
2
3
3
10a (1.35)
10c (1.33)
10d (1.51)
10g (1.41)
10e (1.47)
10f (1.51)
10h (1.29)
94
82
96
95
85
81
80
>20:1
94:6
97:3
94:6
92:8
87:13
91:9
99
99
98
97
99
96
97
1
2
3
4
5
6
7
Ph
mꢀtolyl
pꢀbromophenyl
Ph
pꢀbromophenyl pꢀchlorophenyl
mꢀtolyl pꢀchlorophenyl
aPure crystalline products. bBy 1H NMR. cBy chiral HPLC.
From the mechanistic point of view, we assume that the catalytic cycle operating in the reactions
mediated by 5 is similar to the one proposed by Smith14b for similar reactions mediated by BTM.
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Thus, an acyl ammonium intermediate is formed from the in situ prepared mixed anhydride and the
polystyreneꢀsupported BTM analogue 5. Then, the acyl ammonium species evolves into a Z
ammonium enolate upon deprotonation by the present tertiary amine, and the soꢀgenerated
nucleophile efficiently adds to the Michael acceptor initiating the domino process. While the
9
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configuration of the stereocenter
α to the carbonyl group in 10 appears to be controlled by the
phenyl substituent in the immobilized BTM analogue, as it happens with the homogeneous system,
the reactions mediated by 5 display improved diastereoselectivity with some substrates as we have
already mentioned.14b This behavior can be rationalized (Figure 3) by assuming that the rather bulky
substituent introduced at C3 on the BTM molecule for immobilization purposes further destabilizes
the transition state leading to the formation of the minor cis diastereomer of 10.
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Figure 3. Rationalization of the increased diastereoselectivity in the domino Michael
addition/cyclization reactions mediated by 5.
To further expand the potential of 5 in catalysis, we have briefly examined its use in other reaction
types. While its performance in the kinetic resolution of secondary alcohols11 is rather poor (see
Supporting Information) promising results have been obtained in the formation of βꢀlactams14e
(Scheme 2). Thus, the reaction of 7a with benzaldehyde Nꢀtosylimine 11 mediated by the PSꢀBTM
analogue 5 leads to βꢀlactam with similar diastereoꢀ and enantioselectivity than homogeneous BTM
(Scheme 2).
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5 (15 mol %)
TsCl (1.75 equiv.),
i-Pr2NEt (1.5 +1.5 equiv.)
O
NTs
45% yield. (77% conv.)
>20:1 d.r.
NTs
Ph
+
Ph
CO2H
Ph
(1 equiv.)
CH2Cl2 (0.2 M), 6 h, 0 ˚C
82% ee.
Ph
11
7a (1.1 equiv.)
12
8
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Scheme 2. Preparation of βꢀlactam 12 catalyzed by supportedꢀBTM 5.
3. CONCLUSIONS
In conclusion, we have developed a polystyreneꢀsupported isothiourea organocatalyst (5) based on
the BTM structure. The catalytic resin 5 can be prepared in five simple steps from readily available
enantiopure phenylglycidol (arising from a catalytic Sharpless epoxidation) and displays excellent
performance in the domino Michael addition/cyclization reaction of in situ activated arylacetic
acids with tosylimines derived from chalconeꢀtype enones and from saccharin. The selected
immobilization strategy, involving a functional position innate to the employed synthetic approach,
places the triazole linker and the polystyrene backbone away from the active site. Likewise as a
result of this situation, neither the catalytic activity of 5 nor the stereoselectivity of the reactions it
catalyzes suffers any decrease in comparison with homogeneous BTM. What is more, the
diastereoselectivity recorded with congested arylacetic acids in the studied domino process is far
superior when catalyzed by 5. On top of optimal catalytic performance, the catalytic resin 5 displays
at a high level the sustainability advantages anticipated for immobilized catalysts: recyclability in
batch mode, exemplified by the sequential preparation of a library of the drugꢀlike, enantiopure
tricyclic derivatives 10 at the gram scale, and implementation of a continuous flow process for the
preparation of dihydropyridinone 8a from its ultimate precursors showing substantial improvement
over the corresponding batch process. Further applications of 5, the first immobilized isothiourea
organocatalyst reported so far, are underway in our laboratories.
ASSOCIATED CONTENT
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Supporting Information. Experimental procedures, description of the continuous flow setꢀup,
compound and polymer characterization, NMR spectra and HPLC chromatograms, crystallographic
data for compounds 4, 8a and 10a. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: mapericas@iciq.es; Fax: +34 977920244; Tel: +34 977920243.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was funded by MINECO (grant CTQ2012ꢀ38594ꢀC02ꢀ01), DEC (grant 2014SGR827),
and ICIQ Foundation. We also thank MINECO for support through Severo Ochoa Excellence
Accreditation 2014 – 2018 (SEVꢀ2013ꢀ0319). J. I. thanks PCOFUNDꢀGAꢀ2011ꢀ291787 (ICIQꢀ
IPMP) for a postꢀdoctoral fellowship. The authors thank Mr. Shoulei Wang for experiments
performed at the revision stage.
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(21) For previous examples from this laboratory on the use of catalytically prepared, enantiopure
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1556; (f) MartínꢀRapún, R.; Sayalero, S.; Pericàs, M. A. Green Chem. 2013, 15, 3295–3301.
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(23) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,40, 2004–2021.
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(27) Crystal data are provided in the Supporting Information
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(28) Fukata, Y.; Asano, K.; Matsubara. S. J. Am. Chem. Soc. 2015, 137, 5320 −5323.
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(29) α,αꢀDiphenylacetic acid, αꢀmehylꢀαꢀphenylacetic acid, propionic acid and dihydrocinnamic
acid did not afford any desired product.
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Table of Contents Graphic and Synopsis
A polystyreneꢀsupported isothiourea organocatalyst has been prepared from enantiopure
phenylglycidol and used in the asymmetric domino Michael addition addition/cyclization reaction
of in situ activated arylacetic acids to both cyclic and acyclic conjugated sulfonylimines in batch
and flow.
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