Continuous flow, highly enantioselective Michael additions catalyzed by a PS-supported squaramide

Article abstract of DOI:10.1021/ol400974z

A polystyrene (PS) supported bifunctional squaramide organocatalyst promotes fast Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with very high enantioselectivities at low catalyst loadings. The polystyrene supported catalyst can be recy

Full text of DOI:10.1021/ol400974z

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3498–3501
Continuous Flow, Highly Enantioselective
Michael Additions Catalyzed by a
PS-Supported Squaramide
†
Pinar Kasaplar, Carles Rodrıguez-Escrich, and Miquel A. Pericas*
†
,‡
ꢀ
´
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans 16,
ꢀ
¨
43007 Tarragona, Spain, and Departament de Quımica Organica,
´
Universitat de Barcelona (UB), 08028 Barcelona, Spain
mapericas@iciq.es
Received April 8, 2013
ABSTRACT
A polystyrene (PS) supported bifunctional squaramide organocatalyst promotes fast Michael addition of 2-hydroxy-1,4-naphthoquinone to
nitroalkenes with very high enantioselectivities at low catalyst loadings. The polystyrene supported catalyst can be recycled up to 10 times
without any decrease in enantioselectivity (average 96% ee) and adapted to continuous flow operation (24 h). A single flow experiment involving
six different nitroalkenes in a sequential manner highlights the applicability of this methodology for rapid access to chemical diversity.
The past few years have witnessed a significant increase
in the popularity of supported chiral catalysts.1 The costs
associated with immobilization of catalytically active
species can be compensated by the advantages inherent
to this strategy: ease of recovery and reuse of the catalyst
and, in optimal cases, the possibility of implementing
continuous flow processes.2
In particular, chiral organocatalysts have proven to be
good candidates for immobilization,3 due to their robustness
and their independence of metal cofactors, which suppresses
the possibility of their deactivation by metal leaching. Thus,
† Institute of Chemical Research of Catalonia
‡ Universitat de Barcelona
(1) (a) De Vos, D. V.; Vankelecom, I. F. J.; Jacobs, P. A. Chiral
Catalyst Immobilization and Recycling; WILEY-VCH: Verlag GmbH,
2007. (b) Ding, K.; Uozimi, Y. Handbook of Asymmetric Heterogeneous
Catalysis: Wiley-VCH: Verlag GmbH, 2008.
(3) For early examples with PEG-supported proline, see: (a) Benaglia,
M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal. 2001, 343, 171. (b)
Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisi, A.; Celentano, G. Adv.
Synth. Catal. 2002, 344, 533. For reviews on immobilized organocata-
lysts, see: (c) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103,
3401. (d) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc. Rev.
2008, 37, 1666. (e) Kristensen, T. E.; Hansen, T. Eur. J. Org. Chem. 2010,
3179.
(2) (a) Jas, G.; Kirschning, A. Chem.;Eur. J. 2003, 9, 5708. (b)
Kirschning, A.; Jas, G. Applications of Immobilized Catalysts in Con-
tinuous Flow Processes. In Immobilized Catalysts; Kirschning, A., Ed.;
Springer: Berlin, Heidelberg: 2004; Vol. 242, p 209. (c) Baxendale, I. R.;
Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. K.
Chem. Commun. 2006, 24, 2566. (d) Baxendale, I. R.; Griffiths-Jones,
C. M.; Ley, S. V.; Tranmer, G. K. Chem.;Eur. J. 2006, 12, 4407. (e)
Kirschning, A.; Solodenko, W.; Mennecke, K. Chem.;Eur. J. 2006, 12,
5972. (f) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D.
Angew. Chem., Int. Ed. 2009, 48, 4017. (g) Bedore, M. W.; Zaborenko,
N.; Jensen, K. F.; Jamison, T. F. Org. Process Res. Dev. 2010, 14, 432. (h)
McMullen, J. P.; Stone, M. T.; Buchwald, S. L.; Jensen, K. F. Angew.
Chem., Int. Ed. 2010, 49, 7076. (i) Naber, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2010, 49, 9469. (j) Webb, D.; Jamison, T. F. Chem. Sci.
2010, 1, 675. (k) Noel, T.; Buchwald, S. L. Chem. Soc. Rev. 2011, 40,
5010. (l) Palde, P. B.; Jamison, T. F. Angew. Chem., Int. Ed. 2011, 50,
3525. (m) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011,
47, 4583. (n) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson,
C. R. J. Angew. Chem., Int. Ed. 2012, 51, 4144.
ꢁ
ꢁ
(4) For some examples, see: (a) Calderon, F.; Fernandez, R.;
ꢁ
ꢁ
Sanchez, F.; Fernandez-Mayoralas, A. Adv. Synth. Catal. 2005, 347,
1395. (b) Corma, A.; Garcia, H. Adv. Synth. Catal. 2006, 348, 1391. (c)
Polshettiwar, V.; Baruwati, B.; Varma, R. S. Chem. Commun. 2009,
ꢀ
1837. (d) Riente, P.; Mendoza, C.; Pericas, M. A. J. Mater. Chem. A
€
2011, 21, 7350. (e) Monge-Marcet, A.; Cattoen, X.; Alonso, D. A.;
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Najera, C.; Man, M. W. C.; Pleixats, R. Green Chem. 2012, 14, 1601. (f)
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Riente, P.; Yadav, J.; Pericas, M. A. Org. Lett. 2012, 14, 3668. (g) Yacob,
Z.; Nan, A.; Liebscher, J. Adv. Synth. Catal. 2012, 354, 3259. (h) Garcıa-
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Garcıa, P.; Zagdoun, A.; Coperet, C.; Lesage, A.; Dıaz, U.; Corma, A.
Chem. Sci. 2013, 4, 2006.
r
10.1021/ol400974z
Published on Web 07/09/2013
2013 American Chemical Society

different organocatalysts have been supported on a variety of
inorganic materials and magnetic nanoparticles4 and, most
successfully, on polystyrene (PS) and other organic poly-
mers,5 and continuous flow processes yielding highly enan-
tioenriched products have been implemented with their use.6
We have recently introduced the polystyrene-supported
bifunctional squaramide PS-SQ (Figure 1) for the Michael
addition of β-dicarbonyl compounds to nitroalkenes.7 We
reasoned that, given the fact that the catalytic performance
of squaramides8 is based on hydrogen bonding rather than
in covalent interactions, PS-SQ would be particularly robust
toward deactivation by off-cycle processes and thus appro-
priate for long-term operation under flow conditions. We
wish to report in this letter the development of a continuous
flow, highly enantioselective Michael addition based on
PS-SQ and the implementation with its use of a device for
the sequential preparation of a library of enantiopure adducts.
Michael donor9 in front of nitroalkenes under catalysis by
our polystyrene-supported squaramide.10 Du and co-work-
ers have shown9f that monomeric squaramides efficiently
catalyze the considered Michael addition.
The reaction between 1 and trans-β-nitrostyrene using
CH2Cl2 as the solvent turned out to be fast and clean, and
full conversions were recorded in very short times. Re-
markably, by employing 5 mol % of the supported catalyst
the reaction was complete in less than 20 min yielding 3a in
96% yield and 97% ee. By lowering the catalyst loading to
only 2 mol %, the same results were achieved in 45 min
(Table 1, entry 1). These conditions were considered as
satisfactory and were used for the rest of the batch study.
Table 1. Michael Addition of 2-Hydroxy-1,4-naphthoquinone
with Nitroalkenesa
time
(h)
yield
(%)b
ee
(%)c
entry
R
product
1
C6H5
3a
3b
3c
3d
3e
3f
0.75
1
96
84
89
87
87
89
90
94
87
95
98
91
56
97
96
93
94
95
91
96
95
96
95
95
98
98
2
4-BrC6H4
Figure 1. PS-supported squaramide organocatalyst.
3
4-MeOC6H4
2-BrC6H4
1
4
1
Even if a highly enantioselective supported catalyst has
been developed,7 an additional condition is required for its
practical use in flow: the reactions have to be fast to allow
complete conversion of the reactants with reduced amounts
of catalyst and short residence times. To satisfy this, we
decided to use 2-hydroxy-1,4-naphthoquinone (1) as a
5
3,4-(OCH2O)-C6H3
2-MeOC6H4
2-thienyl
3
6
2
7
3g
3h
3i
2
8
2-furanyl
2.5
1
9
4-MeC6H4
4-FC6H4
10
11
12
13d
3j
1
4-ClC6H4
3k
3l
1
2-phenylethyl
C6H5
1.5
18
ꢀ
(5) (a) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653.
3m
ꢀ
(b) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericas, M. A. Org. Lett. 2007,
a 1(0.2mmol), 2aÀm(0.2mmol), PS-SQ (2mol%) inCH2Cl2 (0.5mL)
at 30 °C. b Isolated yield. c By HPLC. d R2 = Me, dr = 92:8.
ꢀ
9, 3717. (c) Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericas, M. A.
ꢂ
ꢁ
Org. Lett. 2008, 10, 337. (d) Malkov, A. V.; Figlus, M.; Kocovsky, P. J.
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Org. Chem. 2008, 73, 3985. (e) Alza, E.; Pericas, M. A. Adv. Synth. Catal.
2009, 351, 3051. (f) Youk, S. H.; Oh, S. H.; Rho, H. S.; Lee, J. E.; Lee,
J. W.; Song, C. E. Chem. Commun. 2009, 2220. (g) Alza, E.; Sayalero, S.;
Kasaplar, P.; Almas-i, D.; Pericas, M. A. Chem.;Eur. J. 2011, 17, 11585.
(h) Puglisi, A.; Benaglia, M.; Annunziata, R.; Siegel, J. S. ChemCatChem
2012, 4, 972.
(6) (a) Alza, E.; Rodrıguez-Escrich, C.; Sayalero, S.; Bastero, A.;
A series of β-nitrostyrenes bearing either electron-with-
drawing or -donating groups, as well as some 2-hetarylni-
troethylenes, weretestedinthereaction (Table1), and inall
cases products were obtained with very high yields and
enantioselectivities in short reaction times. The reaction of
ꢀ
ꢀ
Pericas, M. A. Chem.;Eur. J. 2009, 15, 10167. (b) Alza, E.; Sayalero, S.;
ꢁ
ꢀ
Cambeiro, X. C.; Martın-Rapun, R.; Miranda, P. O.; Pericas, M. A.
ꢁ
Synlett 2011, 464. (c) Cambeiro, X. C.; Martın-Rapun, R.; Miranda,
ꢀ
P. O.; Sayalero, S.; Alza, E.; Llanes, P.; Pericas, M. A. Beilstein J. Org.
€
€
ꢁ
€ €
Chem. 2011, 7, 1486. (d) Otvos, S. B.; Mandity, I. M.; Fulop, F.
ꢁ
ꢁ
(9) (a) Barcia, J. C.; Otero, J. M.; Estevez, J. C.; Estevez, R. J. Synlett
2007, 1399. (b) Rueping, M.; Sugiono, E.; Merino, E. Angew. Chem., Int.
Ed. 2008, 47, 3046. (c) Zhou, W.-M.; Liu, H.; Du, D.-M. Org. Lett. 2008,
10, 2817. (d) Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhang, G.-C.; Xia,
A.-B.; Xu, X.-S.; Xu, D.-Q. Eur. J. Org. Chem. 2010, 4981. (e) Wu, R.;
Chang, X.; Lu, A.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C.
Chem. Commun. 2011, 47, 5034. (f) Yang, W.; Du, D.-M. Adv. Synth.
Catal. 2011, 353, 1241. (g) Woo, S. B.; Kim, D. Y. Beilstein J. Org. Chem.
2012, 8, 699.
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ChemSusChem 2012, 5, 266. (e) Ayats, C.; Henseler, A. H.; Pericas,
M. A. ChemSusChem 2012, 5, 320. (f) Fan, X.; Sayalero, S.; Pericas,
M. A. Adv. Synth. Catal. 2012, 354, 2971. (g) Bortolini, O.; Caciolli, L.;
Cavazzini, A.; Costa, V.; Greco, R.; Massi, A.; Pasti, L. Green Chem.
2012, 14, 992.
ꢀ
(7) Kasaplar, P.; Riente, P.; Hartmann, C.; Pericas, M. A. Adv.
Synth. Catal. 2012, 354, 2905.
(8) For pioneering works in squaramide-based catalysts, see: (a)
Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130,
14416. (b) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org.
Lett. 2010, 12, 2028. (c) Qian, Y.; Ma, G.; Lv, A.; Zhu, H. L.; Zhao, J.;
Rawal, V. H. Chem. Commun. 2010, 46, 3004. (d) Zhu, Y.; Malerich,
J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153. For reviews on
(10) For squaramide catalysts in nitro group activation, see: (c)
Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450. (d) Bae, H. Y.; Some, S.;
Lee, J. H.; Kim, J.-Y.; Song, M. J.; Lee, S.; Zhang, Y. J.; Song, C. E. Adv.
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Y. S.; Song, C. E. Chem. Commun. 2011, 47, 9621. (f) Marcos, V.;
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Jørgensen, K. A. Chem.;Eur. J. 2011, 17, 6890. (f) Storer, R. I.; Aciro,
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Org. Lett., Vol. 15, No. 14, 2013
3499

para-substituted nitrostyrenes was completed within 1 h
with excellent results (entries 2, 3, 9, 10, 11) regardless of
the electronic nature of the substituent. Heterocyclic ni-
troalkenes bearing a furan and a thiophene moiety were
also found to be good substrates for this reaction (entries 7, 8).
The usually challenging aliphatic nitroalkenes also took part
in the reaction as exemplified by 1-nitro-4-phenyl-1-butene,
which reacted with 1 to give rise to the desired product in
91% yield and 98% ee (entry 12).
Scheme 1. Michael Addition of 1 to 2a in Continuous Flowa
Table 2. Recycling of the PS-SQ in Michael Addition of 1 to 2a
in Batcha
time
yield
(%)b
ee
(%)c
run
(min)
1
2
3
4
5
6
7
8
9
10
20
30
75
90
90
90
90
90
90
90
97
90
90
87
77
85
74
68
76
67
96
96
96
95
96
96
96
96
96
96
a Reaction was performed with 250 mg of resin PS-SQ (0.095 mmol)
and 270 mL of a 0.1 M solution of the reactants in DCM/THF (10:1) at a
0.2 mL minÀ1 flow rate.
3
absence of catalyst, we were even able to pump a solution
of both reagents in CH2Cl2/THF (10:1),11 which simplified
the setup by avoiding the use of a second pump. The
reaction was conducted at room temperature, and prelimin-
ary experiments showed that a flow rate of 0.2 mL minÀ1
3
a The reaction was run with 1a (0.2 mmol), 2a (0.2 mmol), and PS-SQ
(4 mol %) in CH2Cl2 (0.5 mL) at 30 °C. b Isolated yield. c Determined by
chiral HPLC.
was the best compromise between activity and production.
Thus, only 0.095 mmol of catalyst PS-SQ (250 mg, func-
tionalization f = 0.38 mmol gÀ1) was loaded onto the
3
column and the reaction was performed by using 27 mmol
of 1 and a slight excess of 2a (1.2 equiv). After 20 h, 6.6 g of
highly enantioenriched (96% ee) 3a was obtained, which means
As we have previously mentioned, the usefulness of
supported catalysts is associated with their robustness
and, consequently, their capacity to be reused. To test this
capacity in PS-SQ, we performed a recycling study with
the addition of 1 to 2a. After each run, the resin was simply
filtered and washed with CH2Cl2 before reuse. Gratify-
ingly, with only 4 mol % of 1 the system was found to be
active in 10 consecutive runs without any decrease in
enantioselectivity (Table 2). A slight decrease in activity
was observed after the sixth cycle, which can be attributed
to etching of the polymeric matrix upon stirring. Overall,
the product was obtained with 96% ee and 81% yield,
which corresponds to an accumulated TON of 202.
SincePS-SQ fulfilled the requisite characteristics of high
catalytic activity and robustness, the possibility of per-
forming the same reaction in continuous flow was next
tested. The experimental setup consisted of a low-pressure
chromatography column with two adjustable endpieces
(see Supporting Information for details) which was loaded
with the PS-supported squaramide organocatalyst PS-SQ
and connected to a pump used to feed the reactor with the
reagents (Scheme 1).
a TON of 200 and a productivity of 4.07 mmol gresin hÀ1.In
À1
3
3
addition to inherently increased sustainability characteris-
tics arising from workup suppression and highly simplified
scale-up, asymmetric continuous flow processes based on
supported catalysts can offer an additional advantage: the
fast preparation of small libraries of enantiopure com-
pounds. This is a most common need in the early stages of
drug discovery that could be readily satisfied by sequential
synthesis in a flow device. We reasoned that, for its char-
acteristics of high rate and catalyst robustness, the addition
of 1 to a family of nitroolefins 2 mediated by PS-SQ could
be an ideal scenario to assess the feasibility of this approach.
Thus, with a very similar experimental setup we reacted 1
with six different nitroalkenes in a consecutive fashion. Each
substrate/2-hydroxy-1,4-naphthoquinone mixture was cir-
culated through the packed-bed reactor for 1 h (flow rate =
0.2 mL minÀ1), with the column being rinsed by circulation
3
of a mixture of CH2Cl2 and THF (10:1) for 30 min between
two consecutive substrates. The process was repeated up to
It is worth emphasizing that, in this particular case, and
given the fact that no reaction takes place at all in the
(11) The addition of a small amount of THF was necessary to obtain
a homogeneous solution of both reactants.
3500
Org. Lett., Vol. 15, No. 14, 2013

Scheme 2. Continuous Flow Enantioselective Michael Reaction of Six Different Nitroalkenes with 1a
a Reaction was performed with 500 mg of resin PS-SQ (0.171 mmol). A solution of 1 and the corresponding nitroalkene (0.1 M) in 18 mL of CH2Cl2/
THF (10:1) was pumped at a 0.2 mL minÀ1 flow rate. See the Supporting Information for experimental details. b Isolated yield after 1 h run and 30 min
3
rinse with CH2Cl2/THF (10:1). c Determined by chiral HPLC.
six times, and the results of the consecutive flow processes
are summarized in Scheme 2. Remarkably, the correspond-
ing products 3 were prepared with productivities in the
adducts in a single flow experiment with an easily con-
structed and operated asymmetric Michael machine. This
illustrates the unique potential of flow processes based on
covalently immobilized organocatalystsfor theproduction
of libraries of enantiopure compounds. This strategyoffers
significant potential in areas such as medicinal chemistry
or materials science, where small focused libraries of
enantiopure compounds are increasingly demanded.
range 2.04À2.50 mmol gresin hÀ1 which showed no de-
À1
3
3
crease over the whole experiment. Interestingly, this opera-
tion mode can be easily adapted to automatic operation
with the use of standard equipment, thus allowing the
programmable synthesis of small libraries of enantiomeri-
cally pure Michael adducts. Interestingly, products of this
type are precursors of a variety of bioactive compounds.9a,b
In summary the enantioselective Michael addition of
2-hydroxy-1,4-naphthoquinone to nitroalkenes has been
promoted by a polystyrene-supported squaramide cata-
lyst, giving rise to the corresponding products in excellent
yields and enantioselectivities at very low catalyst loadings.
The catalyst has proven highly robust, as exemplified by
multiple recycling and reuse with no drop in enantioselec-
tivity. The batch organocatalytic process has been easily
transferred to continuous flow operation, which has
allowed the sequential preparation of diverse Michael
Acknowledgment. This work was funded by MINECO
(Grants CTQ2008À00947/BQU and CTQ2012-38594-C02-01),
DEC Generalitat de Catalunya (Grant 2009SGR623), and
the ICIQ Foundation. P.K. thanks MINECO for an FPI
fellowship. The authors gratefully acknowledge the staff of
the ICIQ NMR and MS Support Units for their help.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3501