Long-Lived Polymer-Supported Dimeric Cinchona Alkaloid Organocatalyst in the Asymmetric α-Amination of 2-Oxindoles

Article abstract of DOI:10.1021/acscatal.6b01141

Nearly quantitative yields and high enantiomeric purity (89-95% ee) were attained in the course of 100 reaction cycles of a polystyrene resin-supported Cinchona alkaloid organocatalyst in the enantioselective α-amination of 2-oxindoles with diethyl azodicarboxylate. The catalytic material proved stable for >5300 h operation time over 8 months.

Full text of DOI:10.1021/acscatal.6b01141

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Letter
Long-Lived Polymer Supported Dimeric Cinchona Alkaloid
Organocatalyst in the Asymmetric #-Amination of 2-Oxindoles
Ravindra P Jumde, and Alessandro Mandoli
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01141 • Publication Date (Web): 02 Jun 2016
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Long-Lived Polymer Supported Dimeric Cinchona Alkaloid
Organocatalyst in the Asymmetric
Oxindoles
α-Amination of 2-
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Ravindra P. Jumde†,‡,§ and Alessandro Mandoli.*,†,‡
†Dipartimento di Chimica e Chimica Industriale Università di Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
‡ISTM-CNR, Via C. Golgi 19, 20133 Milano, Italy
ABSTRACT: Nearly quantitative yields and high enantiomeric purity (89-95% ee) were attained in the course of 100 reac-
tion cycles of a polystyrene resin-supported Cinchona alkaloid organocatalyst in the enantioselective α-amination of 2-
oxindoles with diethyl azodicarboxylate. The catalytic material proved stable for >5300 h operation time over eight
months.
KEYWORDS: supported organocatalysis, enantioselective catalysis, 2-oxindoles, azodicarboxylates, extended recycling
Introduction
More recently, Hashimoto and co-workers,6 and Opwis,
List and co-workers7 reported impressive durability for a
chiral Rh(I) carboxylate on polystyrene support (100 reac-
tion cycles) and, respectively, a bifunctional Cinchona al-
kaloid derivative on textile fibers (Nylon 6,6; up to 300
reaction cycles).
Inspired by the Merrifield’s idea of solid phase synthe-
sis, the development of supported enantioselective cata-
lysts has been in the pipeline for the past fifty years.1 The
motivations behind these efforts may range from simpli-
fied product purification to the attainment of better cata-
lytic properties. Above all, the possibility of recovering
and re-using the catalyst more and more times stands,
however, as the single most important stimulus to drive
the research in the field. This latter aim has been repeat-
edly acknowledged in the literature, with Gun’ko, Connon
and co-workers suggesting 20 reaction cycles as the min-
imum that would encourage the preparation of insoluble
polymer bound (IPB) enantioselective catalysts "by the
practitioner interested only in its use as a tool”.2 Moreo-
ver, Hübner, de Vries, and Farina recently stressed the
importance of evaluating the productivity increase, if any,
of an IPB system over the corresponding soluble catalyst,
in order to assess its practical advantages in the industrial
perspective.3
While setting new endurance standards in the field of
IPB systems, these examples show nonetheless some limi-
tations when the preparation of the supported catalyst is
examined: In the case of former, the access to a [Rh2(S-
PTTL)4] monomer suitable for immobilization appears
less than optimal for scaling-up because of the statistical
synthetic approach and the need of repeated chromato-
graphic separation for obtaining chiral derivatives and
other styryl intermediates.6 Conversely, the radical graft-
ing employed in the preparation of the textile organocata-
lyst is one of the easiest immobilization methods reported
to date; however, in this case the approach appears
somewhat limited in scope by the low catalyst loading on
the support (max. 0.025 mmol g-1) and the risk of degrada-
tion of the chiral derivative under the 222 nm UV irradia-
tion employed for the grafting.7
Nevertheless, just a few of the IPB systems reported to
date appear to attain the recycling capability noted above
(for selected examples, see refs.2,4) and much less so were
demonstrated to substantially surpass it. Indeed, to the
best of our knowledge only three examples have been dis-
closed, where effective recycling of a supported asymmet-
ric catalyst for more than 50 times was achieved.
These observations prompted us to address the still
pending question whether all the three main features re-
quired for practical usage, i.e. simple and scalable prepa-
ration, satisfactory catalytic performance, and possibility
of extended re-use,8 could be conjugated within a single,
properly designed IPB chiral catalyst architecture.
In an early contribution, Lectka and co-workers at-
tained 60 reaction cycles of a 9-O quinine ester on Wang
resin, in asymmetric [2+2] cycloaddition reactions carried
out in sequentially linked columns.5 However, because
the alkaloid derivative “was employed at undisclosed
loadings (yet considerably higher than 100 mol%)”2 at
least from the practical point of view one of the main ad-
vantages of asymmetric catalysis can be less than obvious
in this example.
In view of the already demonstrated effectiveness of the
synthetic route and their competency in a few organo-
catalyzed asymmetric transformations,4g,9 recently intro-
duced pyridazine Cinchona alkaloid derivatives on poly-
styrene resins were selected for this purpose.
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isolated yield was still modest after an extended reaction
1
time of 64 h and 6a showed lower enantiopurity with re-
spect to the corresponding homogeneous reaction. There-
fore, a brief optimization study was undertaken, which
included examination of the effect of catalyst loading and
substrate concentration. Gratifyingly, doubling the cata-
lyst amount led to some increase in the substrate conver-
sion and product yield in 48 h (Table 1, entry 2), while a
significant improvement of ee’s came by raising [4a] to
0.14-0.20 M (Table 1, entries 3 and 4). Even if the origin of
such an intriguing concentration effect is not clear at pre-
sent, the practical implication of these findings was the
possibility of running AaA reactions with less solvent in
comparison to analogous optimized procedures in the
homogeneous phase (typically 0.1 M in substrate).13b,14-15
Considering the marginally superior ee in the case of [4a]
= 0.14 M, these conditions were adopted in further runs.
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Scheme 1. Preparation of the IPB alkaloid organocat-
alyst 3a and soluble model compound 3b.
The IPB-catalyst 3a was screened next in the AaA of dif-
ferent 1-benzyl-2-oxindoles (Table 1, entries 5-12). Irre-
spective of the C-3 substituent, the corresponding prod-
ucts were obtained in good yield and enantiomeric purity
after a fixed reaction time of 48 h. In detail, substrates
containing (substituted)benzyl (4a,b and 4d-f) and other
unsaturated groups at C3 (4g and 4h) afforded the ami-
nated product with ee values around 90%. The only ex-
ception to this trend was the 3-methoxy derivative 4c
(Table 1, entry 6), whose reaction provided 6c in around
10% lower enantiomeric purity. Some reduction of the ee
was observed also in the reaction of the less hindered 3-
methyl derivative 4i (Table 1, entry 12). Nonetheless, this
latter substrate turned to undergo AaA in a more enanti-
oselective fashion than expected on the basis of literature
precedents (i.e. 76% ee with 10 mol% of the phthalazine
ether 7 in Et2O).13a In the event, the ee value attained with
the IPB-catalyst 3a matched within ±4% that provided
with the same substrate by the soluble model 3b. With
the exception of 4i, noted above, the results proved also
consistent with those afforded by the literature organo-
catalyst 7 under comparable conditions.13a
Results and discussion
The supported quinidine ether 3a was prepared
(Scheme 1) by click-anchoring 1 onto azido-Merrifield res-
in 2a, as described.4g,10 The approach, which takes ad-
vantage of Cu-catalyzed azide–alkyne cycloaddition reac-
tion (CuAAC) for linking chiral units to insoluble polymer
supports,11 confirmed the possibility of obtaining the im-
mobilized catalyst through steps that do not require
chromatographic purifications at any stage. Interestingly,
on the larger scale and with the extended reaction time
adopted in the present investigation, 3a was obtained
with an alkaloid loading (0.70 mmol g-1 or 53% by weight)
that was significantly larger than achieved before.
Given that 3-amino-2-oxindoles with a quaternary ste-
reocenter are known to be key building-block for biologi-
cally active compounds and clinical candidates, their syn-
thesis using affordable catalytic procedures is actively
sought.12 With this goal in mind, the organocatalytic
asymmetric α-amination (AaA) of 2-oxindoles, developed
independently by the groups of Barbas III,13 Chen,14 and
Zhou,15 was chosen as a convenient playground for evalu-
ating the recyclability of the IPB Cinchona derivative.
Following an initial lead,9 examination of the soluble
model 3b of the supported alkaloid units confirmed that
the pyridazine central spacer could stand as an effective
replacement of the phthalazine one in some of the litera-
ture catalysts.13,15 In particular, optimization of the origi-
nal conditions of Barbas III and co-workers13a revealed
that 3b performed best when the AaA of N-benzyl pro-
tected 2-oxindoles 4a-i with diethyl azo-dicarboxylate
(DEAD, 5) was carried out in moderately concentrated
(0.08-0.14 M) THF solutions (see SI, Table S1).
Because promising endurance already emerged from
recycling of 3a in the initial substrate screening (see Table
1), the central issue of its extended re-use could be ad-
dressed next. In order to facilitate the evaluation of trends
in activity and stereoselectivity, 4a was selected as a fixed
2-oxindole substrate and catalyst 3a, recovered from pre-
vious runs (Table 1, entries 2-4 and Figure 1, cycles 1-3),
was repeatedly employed under optimized conditions.
Quite surprisingly, additional cycles initially afforded
6a in disappointingly variable yields (Figure 1, cycles 4-
30). After examining the possible causes, the culprit was
identified in the fluctuation of the room temperature at
night. For this reason, further catalysis experiments were
carried out by thermostating the reaction vessel at 29°C.
Much to our delight, under these conditions the appar-
ently erratic behavior was not observed anymore and the
aminated product 6a was consistently obtained in nearly
quantitative isolated yield and >90% ee, throughout the
entire series of new reaction runs (Figure 1, cycles 31-100).
Thanks to the excellent swelling of polystyrene resins in
THF, these results opened the way to the study of the cor-
responding heterogeneous reactions (Table 1). Therefore,
4a in THF was exposed to 5 in the presence of 10 mol% of
the supported catalyst 3a. When the reaction was initially
performed at [4a] = 0.08 M, the expected aminated prod-
uct 6a formed smoothly (Table 1, entry 1). However, the
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Table 1. Results in the heterogeneous AaA of 1-benzyl-2-oxindoles.
1
2
3
4
5
NHCOOEt
NCOOEt
R
R
EtOOC
N
N
Cat. 3a
O
O
N
COOEt
THF, r.t., 48 h
N
Bn
Bn
6
5
4a-i
6a-i
7
8
9
Entry
Catal. (mol%) Substrate (R)
C (M)a
0.08
Prod.
Yield (%)b,c
51 (90)
ee (%)c,d
92 (96)
92
1e
10
4a (Bn)
6a
6a
6a
6a
6b
6c
6d
6e
6f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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2
20
4a (Bn)
0.08
0.14
0.20
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
72
3
20f
20f
20
4a (Bn)
81 (90)
95 (96)
93
4
5
4a (Bn)
>95
4b (4-Me-Benzyl)
84 (>95)
>95 (>95)
93 (>95)
>95 (>95)
>95 (>95)
92 (>95)
91 (>95)
>95 (>95)
91 (91)
81 (85)
91 (89)
89 (89)
91 (92)
91 (91)
89 (87)
85 (86)
6
7
20f
20f
20f
20f
20f
20f
20f
4c (3-MeO-Benzyl)
4d(4-MeO-Benzyl)
4e (4-Cl-Benzyl)
4f (4-F-Benzyl)
4g (Allyl)
8
9
10
11
12
6g
6h
6i
4h (E-Cinnamyl)
4i (Me)
Substrate concentration. b Isolated yield after flash chromatography. In parentheses, data obtained under comparable condi-
a
c
d
e
tions with the soluble model catalyst 3b. By chiral HPLC; the prevailing enantiomer had (S) configuration (see SI). Reaction
run for 64 h. f Recycled IPB organocatalyst from the previous run.
Because these results confirmed the possibility of using
3a more and more times, it became interesting to contrast
its overall performance with that of the soluble alkaloid
derivative 7 from the literature. For the reasons discussed
elsewhere,16 this comparison involved the assessment of
enantioselectivity and productivity P (= mol of product
per mol of catalyst employed)17,18 in the homogeneous re-
action, as functions of catalyst loading. Hence, the AaA of
4a with 5 was studied with progressively diminishing
amounts of 7, under conditions otherwise analogous to
those employed in the heterogeneous experiments.
The outcome of these runs (Figure 2) showed that the
homogenous process can tolerate 20-fold reduction of
catalyst loading below the reported literature value (10
mol%),13a before erosion of the enantiomeric purity of
product 6a becomes noticeable. At the same time, how-
ever, the reaction rate was largely impaired under these
conditions. This was especially evident towards the low-
end side (0.1-1 mol%), where dramatically reduced sub-
strate conversion and product yield were recorded at 48
h, or even after an extended reaction time of 300 h.
Therefore, even if the data in Figure 2 actually translate
into progressively increasing P at lower loadings (e.g.
P@ee=61@93% with 1 mol% of 7, see Figure 3), such an
approach to the intensification of the homogeneous pro-
cess is clearly not viable below the 5 mol% threshold.
100
90
yield
80
ee
70
a
b
c
60
50
40
0
10
20
30
40
50
Cycles
60
70
80
90
100
Figure 1. Recycling of 3a in the heterogeneous AaA of 4a.
Conditions: For cycles 1-3 (a), see Table 1, entries 2-4; for the
other runs, 20 mol% 3a, 1.2 equiv. 5, THF, [4a] = 0.14 M, 48 h
(65 h during week-end), and T=19-27°C (b) or T=29°C (c).
Figure 2. AaA of 4a in the presence of variable amounts of
the soluble organocatalyst 7 (for the conditions, see Figure 1c;
data at 0.1-1 mol% catalyst loading were obtained with 300 h
reaction time).
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By contrast, the demonstrated endurance of 3a led to
Page 4 of 7
100
90
80
70
60
50
40
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2
3
4
5
6
7
8
smooth increase of cumulative productivity Pn (see Figure
3), which indeed reached P100@ee=484@93% (equivalent
to approx. 0.2 mol% effective catalyst usage) at the end of
the series. Because 7 provides no more than P=10-16 under
acceptable conditions (5 -10 mol% loading, see Figure 2),
the results for 3a correspond to a larger than 30-fold in-
crease of product obtained with a given initial amount of
the chiral derivative. Rather obviously, this achievement
was made possible by the straightforward recovery of 3a
by filtration and by the fact that, according to Figure 1, an
average catalyst loss significantly lower than 1% per cycle
can be safely inferred. Therefore, even if the recovery of 7
by various techniques (e.g. solvent extraction or chroma-
tography) is certainly possible, it appears unlikely that the
accomplishment of such a task for the soluble catalyst
(and the subsequent increase of productivity on re-use)
would be as effective as for 3a.
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0
100
200
P or Pn [mol/mol]
300
400
500
Figure 3. Enantioselectivity vs. productivity for 7 at different
loadings (broken curve) and in the recycles of 3a (20 mol%;
solid curve) in the AaA of 4a. (for the conditions, see Figure
1; for the meaning of P, Pn, and ee, see the text).
Another aspect that deserves a comment is the fact that
the reaction cycles summarized in Figure 1 involved expo-
sure of 3a to reactants and solvents for >5300 h, over eight
months. This choice was not dictated by poor perfor-
mance of the IPB catalyst with respect to its soluble coun-
terparts,19 but was just a consequence of the relatively
slow kinetics of the organocatalytic transformation under
exam.13a In any case, the circumstance gave the opportuni-
ty to examine recycling of a polystyrene-supported cata-
lyst for a time span longer than ever before, including the
recalled investigation of Hashimoto and co-workers (ap-
prox. 33 h, according to published data).6 Besides con-
firming the high chemical stability of the linkages em-
bedded in 3a, the most remarkable observation in this re-
spect was that the polymeric material could stand pro-
longed stirring (albeit at low speed, 40-60 rpm), without
troublesome filtration and incomplete recovery caused by
breaking to fines. Contrarily to the common concern that
Merrifield-type resins are very prone to mechanical wear-
ing,20 unless special techniques (e.g. “tea-bag”) are adopt-
ed,21 it seems then that under favorable conditions – par-
ticularly the low stirring rate in the present investigation-
their serviceability can extend much beyond what gener-
ally believed.
Rather obviously, the result would had not been possi-
ble if the chiral derivative itself underwent appreciable
chemical degradation in the reaction mixture. In this re-
spect, it can be speculated that the base-catalysis mecha-
nism proposed for Cinchona alkaloids13a,14 is well fit for
avoiding potentially deactivating intermediates like, e.g.,
those involved in the related AaA of linear aldehydes with
supported diphenylprolinol organocatalysts.24,25
Instrumental to the attainment of extended operational
life was also the robustness of the linkage between chiral
units and polystyrene resin and, more in general, of the
catalytic material as a whole. In turn, this allowed to
demonstrate that multi-thousand hour endurance is not
limited to the photochemically grafted Nylon fibers by
Opwis, List and co-workers,7 but is a sizeable possibility
also for IPB organocatalyst prepared by more convention-
al bench-top techniques.
In conclusion, we feel that the main achievement of the
present study stands in the demonstration that scalable
synthesis, satisfactory activity, excellent asymmetric in-
duction, and extended recycling could be conjugated, for
the first time, into a single IPB catalyst architecture. Giv-
en the excellent serviceability of 3a, analogous supported
Cinchona alkaloid derivatives are currently under exam
for their use in continuous-flow reactors.
Finally, it has to be mentioned that a single recrystalli-
zation from MTBE of pooled samples of 6a was sufficient
for obtaining >99% ee product in the mother liquor (85%
yield) and a small amount of crystals with lower ee (22%).
Hence, even though the enantioselectivity degree of the
heterogeneous reaction proved somewhat reduced in
comparison with the use of 7 in the homogeneous phase
(96-99% ee, see SI, Table S1 and ref.13a), the behavior of
the enantiomers of 6a upon crystallization eventually al-
lowed the isolation of the product in high enantiomeric
purity.22,23
ASSOCIATED CONTENT
Supporting Information (SI): Synthetic procedures and char-
acterization details (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: alessandro.mandoli@unipi.it. Telephone: +39
0502219280. Fax: +39 0502219260
Concluding remarks
In summary, the present study adds a third entry to the
very limited set of enantioselective IPB catalytic systems
for which effective recycling in the three-digits range
could be demonstrated.
Present address
§ Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
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Notes
ACS Catalysis
2008, 5-15. (g) Jumde, R. P.; Mandoli, A.; De Lorenzi, F.;
1
2
Pini, D.; Salvadori, P. Adv. Synth. Catal. 2010, 352, 1434-
1440. (h) Arakawa, Y.; Wiesner, M.; Wennemers, H. Adv.
Synth. Catal. 2011, 353, 1201-1206. (i) Oohara, T.;
Nambu, H.; Anada, M.; Takeda, K.; Hashimoto, S. Adv.
Synth. Catal. 2012, 354, 2331-2338. (j) Ötvös, S. B.;
Mándity, I. M.; Fülöp, F. J. Catal. 2012, 295, 179-185.
(5) Hafez, A. M.; Taggi, A. E.; Dudding, T.; Lectka, T. J.
Am. Chem. Soc. 2001, 123, 10853-10859.
(6) Takeda, K.; Oohara, T.; Anada, M.; Nambu, H.;
Hashimoto, S. Angew. Chem. Int. Ed. 2010, 49, 6979-6983.
(7) Lee, J.-W.; Mayer-Gall, T.; Opwis, K.; Song, C. E.;
Gutmann, J. S.; List, B. Science 2013, 341, 1225-1229.
(8) Kristensen, T. E.; Hansen, T. In Catalytic Methods in
Asymmetric Synthesis; Gruttadauria, M., Giacalone, F.,
Eds.; John Wiley & Sons: 2011, p 209-256.
The authors declare no competing financial interest.
3
Funding Sources
4
5
6
7
8
9
Financial support by the Università di Pisa (PRA_2016_46
"Studio di sistemi confinati: verso un approccio multiscala")
and by MIUR (FIRB Project RBFR10BF5V “Multifunctional
hybrid materials for the development of sustainable catalytic
processes”). R.P.J. was supported by “Scuola Galilei”, Univer-
sità of Pisa (Ph.D. grant), and by ISTM-CNR (post-doc re-
search contract).
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ACKNOWLEDGMENT
Dedicated to Prof. Dario Pini on the occasion of his 75th
birthday.
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(10) For the general methods, materials, analytical
procedures, characterization data and the preparation of
substrates and IPB-catalysts, see the Supporting
Information.
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(17) In the absence of a specific IUPAC definition, other
than for the biotechnological field (see ref. 18a), the term
‘productivity’ has been used in the literature in connection
with both time-related (e.g. average turnover frequency at
reaction end, TOF) and time-independent features of a
catalyst (e.g. total turnover number, before de-activation or
upon recycling, TTON). For examples in either sense, see
refs. 18b-d. Because the focus of the present investigation
was about catalyst durability, the latter meaning is adopted
herein (for the use of the symbol P in similar context, see
ref. 18e).
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(18) (a) McNaught, A. D.; Wilkinson, A. IUPAC.
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Book"). XML on-line corrected version; Blackwell
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Int. J. Chem. Eng. Appl. 2014, 5, 6-12. (d) Sattler, A.;
Aluthge, D. C.; Winkler, J. R.; Labinger, J. A.; Bercaw, J.
E. ACS Catalysis 2016, 6, 19-22. (e) McNair, R. J. In
Catalysis of Organic Reactions; Scaros, M. G., Prunier, M.
L., Eds.; Dekker: New York, 1995, p 1-11.
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(19) Concerning catalytic activity, 3a (average TOF ≈ 0.1
h-1) proved less effective than the other two long-lived
supported systems mentioned in the Introduction. This is
especially true in comparison with the Rh(I) carboxylate by
Hashimoto and co-workers (average TOF around 135 h-1,
see ref. 6). As shown by the soluble derivatives 3b and 7,
these differences are not due to immobilization effects but
are just a consequence of the low specific activity of the
alkaloid derivatives in the AaA reaction under exam. While
high turnover rate is clearly an ideal requisite of any
catalytic system, we feel that the circumstances met in the
present study are exactly where the availability of easily
prepared and robust IPB systems can prove beneficial the
most. In particular, the possibility to recover and reuse the
valuable chiral inductor for hundred times -with a
procedure as simple as a filtration- may help in lifting one
of the main drawbacks of many enantioselective metal-free
homogenous systems reported to date, i.e. the need of large
loadings of the expensive chiral organocatalyst for
balancing slow reaction kinetics.
(20) Kasaplar, P.; Riente, P.; Hartmann, C.; Pericàs, M. A.
Adv. Synth. Catal. 2012, 354, 2905-2910.
(21) (a) Houghten, R. A. Proc. Natl. Acad. Sci. U. S. A.
1985, 82, 5131-5135. (b) Comina, P. J.; Beck, A. K.;
Seebach, D. Org. Process Res. Dev. 1998, 2, 18-26.
(22) Unless a "true racemate" with eutectic compositions
very close to 100% ee is supposed, the phenomenon does
not fit typical phase diagrams for mixtures of enantiomers
(see ref. 23). Nevertheless, a similar behaviour has been
previously reported by Zhou and co-workers (ref.15). At
variance with the literature study, where the very strong
tendency of the racemate to crystalize was related to a
network of hydrogen bonds involving also the unprotected
2-oxindole N-H fragment, the findings of the present study
suggest that it might be a more general feature of this class
of chiral compounds, including those with protected
endocyclic nitrogen.
(23) J. Jaques, A. C., S. H. Wilen Enantiomers,
Racemates, and Resolutions; J. Wiley & Sons: New York,
1981.
(24) Fan, X.; Sayalero, S.; Pericàs, M. A. Adv. Synth.
Catal. 2012, 354, 2971-2976.
(25) For
a
stable supported bifunctional thiourea
organocatalyst in the AaA of 1,3-dicarbonyls, see:
Kasaplar, P.; Ozkal, E.; Rodriguez-Escrich, C.; Pericas, M.
A. Green Chem. 2015, 17, 3122-3129.
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