Enantioselective continuous-flow production of 3-indolylmethanamines mediated by an immobilized phosphoric acid catalyst

Article abstract of DOI:10.1002/chem.201303860

A polystyrene-supported 1,1'-bi-2-naphthol derived phosphoric acid has been synthesized and applied in the enantioselective Friedel-Crafts reaction of indoles and sulfonylimines. The immobilized catalyst was highly active and selective, and gave rise to a

Full text of DOI:10.1002/chem.201303860

DOI: 10.1002/chem.201303860
Full Paper
&
Catalysis
Enantioselective Continuous-Flow Production of
3-Indolylmethanamines Mediated by an Immobilized Phosphoric
Acid Catalyst
Laura Osorio-Planes,[a] Carles Rodrꢀguez-Escrich,[a] and Miquel A. Pericꢁs*[a, b]
Abstract: A polystyrene-supported 1,1’-bi-2-naphthol de-
rived phosphoric acid has been synthesized and applied in
the enantioselective Friedel–Crafts reaction of indoles and
sulfonylimines. The immobilized catalyst was highly active
and selective, and gave rise to a broad range of 3-indolyl-
methanamines (19 examples) in high yields and excellent
enantioselectivities (up to 98% enantiomeric excess) after
short reaction times under very convenient reaction condi-
tions (RT in dichloromethane). Moreover, repeated recycling
(14 cycles) was possible with no substantial loss in catalytic
performance and the system could be adapted to a continu-
ous-flow operation (6 h). Finally, the applicability of the
system was further confirmed by rapid access to a library of
compounds with three points of diversity in a single contin-
uous-flow experiment that involved sequential pumping of
different substrate combinations.
Introduction
In recent years, 1,1’-bi-2-naphthol (BINOL)-derived phosphoric
acids (PA) have emerged as powerful and versatile catalysts for
many asymmetric transformations.[1] Such catalysts bear both
a Brønsted acidic (PÀOH) and a Lewis basic site (P=O) that can
act cooperatively, which makes them unique candidates to
promote a large variety of organic reactions. Moreover, they
are air stable and can be easily stored. However, to achieve op-
timum enantiodifferentiation, bulky substituents are required
at positions 3 and 3’,[1a,d] which infers multistep syntheses and,
therefore, an increased cost of the catalysts. Consequently, we
thought that it would be highly desirable to immobilize the
catalyst onto a solid support (Scheme 1) to allow recovery and
reuse.
Scheme 1. Schematic representation of the immobilized chiral phosphoric
acid.
nation.[4] Recently, the same group have reported the use of
a chiral phosphoric acid in a flow system,[5] but in this case the
catalyst was pumped in solution and, thus, the advantages of
a supported catalyst could not be fully exploited.
Interest in the immobilization of homogeneous chiral cata-
lysts onto different solid supports has spread in recent years
due to an increase in environmental concerns in the practice
of organic synthesis.[2] It is well known that these immobilized
catalysts present the additional advantages of easy product
isolation, recyclability, and the possibility of use under continu-
ous-flow conditions.[3] Rueping et al. already envisioned these
potential advantages by development of a PA polymeric stick
that could be applied in catalytic asymmetric transfer hydroge-
The enantioselective Friedel–Crafts alkylation of indoles and
aldimines has proven to be one of the most important CÀC
bond-forming reactions in modern organic chemistry because
the resultant 3-indolylmethanamine derivatives are structural
motifs for many biologically active natural and natural-like
products.[6] A variety of organocatalytic systems that involve
chiral Brønsted acids have been successfully developed to
carry out this transformation.[7–9] A highlight among them is
the work developed by You et al., in which a BINOL-derived
phosphoric acid efficiently catalyzed this reaction with very
high enantioselectivities.[10]
[a] L. Osorio-Planes, Dr. C. Rodrꢀguez-Escrich, Prof. Dr. M. A. Pericꢁs
Institute of Chemical Research of Catalonia (ICIQ)
Av. Pa¨ısos Catalans, 16, 43007 Tarragona (Spain)
Fax: (+34)977-920-243
E-mail: mapericas@iciq.es
Herein, we now report the easy and reproducible synthesis
of a polystyrene (PS) supported BINOL-derived PA and its use
as a highly enantioselective and recyclable catalyst for the
Friedel–Crafts reaction of sulfonylimines and indoles.
[b] Prof. Dr. M. A. Pericꢁs
Departament de Quꢀmica Orgꢁnica
Universitat de Barcelona, 08080 Barcelona (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303860.
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Results and Discussion
Table 1. Screening of the reaction conditions.
From previous experience in our laboratory, we planned to im-
mobilize at a remote position to avoid perturbation of the
active site of the catalyst.[11] (R)-6-Hydroxymethyl- 2,2’-bis(me-
thoxymethyloxy)-1,1’-binaphthalene (1) was synthesized from
commercially available (R)-BINOL by a reported procedure.[12]
Compound 1 was converted to the 6-hydroxymethyl derivative
5 in four steps and, subsequently, this monomer was anchored
onto a Merrifield resin by nucleophilic substitution of the
chlorine atoms (Scheme 2). After fine-tuning the reaction con-
ditions, a quantitative functionalization could be achieved by
addition of an excess of BINOL-derivative 5. Very conveniently,
unreacted 5 could be further recovered from the solution after
separation of the resin by filtration. The use of a triazole linker,
introduced by click chemistry,[13] was also considered as an al-
ternative approach for this immobilization.[14] However, this
Entry
Cat. loading
[mol%]
t
[h]
Indole
[equiv]
Conv.
[%][b]
Yield
[%][c]
ee
[%][d]
1[a]
2
3
4
5
6
7[e]
8
8
2.5
21
21
5
5
6
1.3
1.3
1.3
2
3
1.5
1.5
>99
91
97
>99
>99
98
96
63
63
92
95
77
81
85
97
97
92
91
94
93
16
10
10
10
10
2.5
>99
[a] Toluene was used as the solvent. [b] Conversion was determined by
1H NMR spectroscopy. [c] Yield of the isolated product. [d] Enantiomeric
excess was determined by chiral HPLC analysis with a Chiralcel OD-H
column. [e] c=0.16m.
The first parameter to be eval-
uated was the solvent. Although
the reaction proved to be faster
in toluene than in CH2Cl2, the
enantiomeric excess (ee) turned
out to be substantially lower (85
vs 97% ee; Table 1, entries 1 and
2). Therefore, CH2Cl2 was the
preferred solvent for further
screening. An increase in the
equivalents of indole resulted in
much shorter reaction times, as
well as higher yields (Table 1, en-
tries 4–6), whereas doubling the
catalyst loading did not lead to
any significant improvement
Scheme 2. Synthesis of the immobilized catalyst: a) imidazole, TBSCl (quant.); b) BuLi, Br2 (70%); c) 3,5-
(CF3)2C6H3B(OH)2, [Pd2(dba)3], SPhos, K3PO4 (86%); d) TBAF (89%); e) Merrifield resin (0.5 mmolgÀ1), NaH, Bu4NI
(quant. functionalization); f) HCl/EtOAc (2m); g) POCl3 and pyridine, then HCl (1n, 70%); MOM=methoxymethyl,
dba=dibenzylidene acetone, SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, TBAF=tetrabutylammo-
nium fluoride.
(Table 1, entry 3). Finally, when
the reaction was performed at
higher concentration (imine: c=
0.16m) only a slight excess of
indole was required and good
yield (81%) and excellent enan-
strategy was finally abandoned due to reproducibility issues,
likely ascribable to triazole-catalyzed background reaction. The
final heterogeneous catalyst 8 was obtained after cleavage of
the methoxymethyl ether (MOM) groups and subsequent
phosphoric acid formation. We reasoned that if the latter trans-
formation was performed after the immobilization step the pu-
rification of the resulting Brønsted acid would be greatly sim-
plified: excess reagents could simply be washed off. Indeed,
one of the main problems in the preparation of phosphoric
acids is product isolation, which can lead to the formation of
undesired species.[15]
tioselectivity (93% ee) were obtained after only 2.5 h (Table 1,
entry 7). We were very pleased to see that the results obtained
with the PS-supported catalyst 8 were comparable to those re-
ported with a homogeneous phosphoric acid catalyst.[10] Re-
markably, when catalyst 8 was used, good enantioselectivities
were obtained at room temperature, instead of the rather in-
convenient À608C previously described. Moreover, with our
system a large amount of indole could be saved because only
1.5 equivalents were necessary, in sharp contrast with the
5 equivalents required in the homogeneous reaction.
Once the reaction conditions were optimized, one of the
main aims of this work was addressed: the recyclability of the
immobilized catalyst. To our delight, the catalyst not only
proved to be highly recyclable (six cycles) but could also be re-
activated by a simple acidic wash when a small drop in activity
With the supported catalyst in hand, we proceeded to
screen different parameters for the aza-Friedel–Crafts reaction
with the tosylimine derived from benzaldehyde and indole as
model substrates.
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phosphoric acid 8. Interestingly, almost enantiopure 10a was
recovered after 24 h (95% ee, 24% yield); after 3 h, 10a
(66% ee, 50% yield) was obtained (Scheme 4). Indeed, similar
kinetic resolutions have been previously reported with indole[9]
or N-methylindole[16c] as the nucleophile.
Scheme 4. Kinetic resolution of 10a with indole.
The next step was to explore the scope of the reaction. With
regard to tosylimines (Scheme 5) good-to-excellent yields and
enantioselectivities were observed with imines derived from
both electron-poor (10b, 10c, 10h) and electron-rich (10d,
10e, 10g) benzaldehydes. Ortho substituents resulted in
longer reaction times (10 f). Analogously to what has been re-
ported with related homogeneous catalysts,[8b–c,10,16j–k] PS-sup-
ported phosphoric acid 8 was limited to aromatic imines as
substrates; very poor performance was observed with an ali-
phatic imine (10i).
Figure 1. Recycling experiments.
was observed. Notably, the reactivated resin was even more
active than the initial one, which allowed for seven more
cycles without any significant loss in activity or enantioselectiv-
ity, in shorter reaction times (Figure 1). On the fourteenth
cycle, the resin still showed excellent levels of activity (91%
yield, 90% ee obtained after 2 h). We reasoned that the acidic
treatment in EtOAc might have protonated traces of phos-
phate salt that remained after phosphoric acid formation.
Thus, we decided to include HCl/EtOAc washings as the last
stage of the resin preparation.
It is important to mention that the difference between con-
version (100%) and yield in the experiments shown in Figure 1
is due to the formation of bis(indolyl)methane 9 as a by-prod-
uct (Scheme 3), which is generally observed in acid-catalyzed
Scheme 5. Scope of the tosylimine. Reaction conditions: tosyl imine
(0.07 mmol), indole (0.1 mmol), catalyst 8 (10 mol%), CH2Cl2 (0.45 mL), RT.
[a] Indole (3 equiv) was used to minimize by-product formation. [b] Conver-
sion=82%.
Scheme 3. Proposed mechanism for the formation of by-product 9.
Remarkably, when the reaction was performed with bisimine
11 the C2 symmetric double-adduct 10j, which offered ample
opportunity for further functionalization, could be obtained
with very high enantioselectivity (95% ee) after only 15 min
(Scheme 6).
aza-Friedel–Crafts reactions.[10,16] Careful analysis of the results
summarized in Figure 1 revealed an interesting trend: experi-
ments that gave lower isolated yields provided the best enan-
tioselectivities. This indicated that a kinetic resolution was
taking place. According to our hypothesis, the destruction of
the final product 10a would be assisted by the chiral PA, with
a higher decomposition rate for the minor enantiomer (R)-10a
(Scheme 3).
The absolute configuration of 10j (Figure 2) was confirmed
to be (S,S) by single-crystal X-ray diffraction.[17] The configura-
tion of the rest of the molecules reported herein was assigned
by analogy to this compound and in accordance with previous
reports from the literature.[18]
To confirm this hypothesis, racemic 3-indolylmethanamine
10a was treated with indole (0.6 equiv) and PS-supported
The use of substituted indoles, as well as imines other than
tosylimine was also examined. The results are summarized in
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products obtained have not been previously reported.[19]
Once the recyclability and versatility of resin 8 were success-
fully evaluated and, in view of its high catalytic activity, trans-
lated into remarkable reaction times, we decided to study the
implementation of a single-pass, continuous-flow Friedel–
Crafts reaction of indole and the tosylimine derived from p-
tolualdehyde. The experimental setup consisted of a Teflon
Scheme 6. Enantioselective aza-Friedel–Crafts reaction with bisimine 11.
tube (1= -inch diameter) with two adjustable endpieces, loaded
4
with PS-supported phosphoric acid 8 and connected to two
syringe pumps that fed the column with the respective re-
agents. This system had to be equipped with a backpressure-
regulator device to avoid the formation of bubbles that origi-
nated from the use of CH2Cl2 as solvent. Furthermore, in situ IR
spectroscopy could be performed to get qualitative informa-
tion on the extent of the reaction (Figure 3).[20] Thus, the ab-
sence of the band at n˜ =1600 cmÀ1 (starting imine) was taken
as an indication of full conversion.
Figure 2. Single-crystal X-ray structure of (S,S)-10j.
Table 2. The reactions proceeded smoothly and af-
forded the products in high yields and enantioselec-
tivities, regardless of the electronic properties and
substitution pattern of the indole (Table 2, entries 1–
4). Very good results were also achieved when ben-
zene sulfonylimine was the substrate; remarkably, the
reaction was complete after only 45 min (Table 2,
entry 5). We were very pleased to observe that this
system could be also applied to a range of 2-pyridyl
sulfonylimines (Table 2, entries 6–9). Although longer
reaction times were usually required in these cases, it
is important that, to the best of our knowledge, the
Figure 3. Continuous-flow setup. Inset: column.
Table 2. Scope of indoles and sulfonylimines.[a]
To maintain the optimized conditions from the batch synthe-
sis, solutions of imine (c=0.32m) and indole (c=0.48m) in
CH2Cl2 were pumped through a column loaded with 8 (0.36 g,
f=0.25 mmolgÀ1, 0.09 mmol) at a combined flow rate of
0.2 mLminÀ1. The system was submitted to continuous-flow
operation for 6 h and, to our delight, both conversion and
enantioselectivity remained high throughout the entire process
(conversionꢀ97%, eeꢀ91%; Figure 4).
Entry
Ar
R
R’
t
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
Ph
Ph
Ph
Ph
4-tolyl
4-tolyl
4-tolyl
4-tolyl
Ph
5-MeO
5-Me
5-Br
6-Cl
H
1.5
0.75
1.5
2.5
0.75
24
24
20
3
89
84
90
92
83
90
84
81
84
90
97
84
90
94
90
77
83
84
In this single continuous-flow operation, highly enantioen-
riched compound 10d (94% ee) was isolated in 80% (3.6 g)
overall yield, which represents a turnover number (TON) of 102
5
Ph
6[d]
7[d]
8[d]
9
Ph
2-Py
2-Py
2-Py
2-Py
H
H
H
H
À1
and a productivity of 4.3 mmolh
g
À1. In other words, the
resin
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
catalyst loading of the global process was as low as 0.8 mol%
(with a residence time of 9.3 min), which is more than a twelve-
fold decrease with respect to the batch conditions.
[a] Reaction conditions: sulfonylimine (0.07 mmol), indole (0.1 mmol), cat-
alyst 8 (10 mol%), CH2Cl2 (0.45 mL), RT. [b] Yield of the isolated product.
[c] Enantiomeric excess was determined by chiral HPLC analysis with
a Chiralcel OD-H or Chiralpak IA column. [d] Reaction conditions: 2-pyri-
dyl sulfonylimine (0.04 mmol), indole (0.05 mmol), catalyst 8 (8 mol%),
CH2Cl2 (0.5 mL), RT. Py=pyridine.
Taking into account the inherent advantages of using con-
tinuous-flow systems (such as workup suppression and simpli-
fied scale-up) and in view of the biological importance of the
resultant 3-indolylmethanamines,[5] we next explored the prep-
aration of a small library of enantioenriched compounds. This
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Figure 5. Enantioselective continuous-flow production of a library of 3-indo-
Figure 4. Continuous-flow enantioselective Friedel–Crafts reaction catalyzed
by 8.
À1] are shown in parentheses.
À1
lylmethanamines. Productivities [mmolh
g
resin
is a common need in the early stages of drug discovery that
could be readily satisfied by sequential synthesis in a flow
device. Thus, by using the same continuous-flow setup, combi-
nations of different sulfonylimines and indoles were passed
through the packed-bed reactor in a consecutive fashion. Each
has shown to promote kinetic resolution of a racemic 3-indo-
lylmethanamine. A single-pass, continuous-flow process could
be implemented to allow easy scale-up. In addition, the versa-
tility of our approach has been demonstrated in the rapid and
convenient production of a library of enantioselective com-
pounds. To the best of our knowledge, this constitutes the first
continuous-flow application of a supported chiral phosphoric
acid. Taking into account the cost of their homogeneous coun-
terparts, as well as the robustness of the catalytic resin intro-
duced, we believe this method represents an interesting alter-
native for the scale-up of enantioselective processes mediated
by BINOL-derived phosphoric acids. Efforts towards the prepa-
ration of analogous supported chiral phosphoric acids and
their application to other reactions are currently underway in
our laboratory.
of them was run for 1 h (combined flow rate=0.2 mLminÀ1
)
and the column was rinsed by circulation of CH2Cl2 for 30 min
between each pair of reagents. The process was repeated for
five different combinations of indole donor and imine accept-
or, the results of which are summarized in Figure 5.
À1
Very high productivities (4.3–5.0 mmolh
g
À1) were ob-
resin
tained with all the substrates tested. Furthermore, an elevated
degree of variability was achieved in the library of compounds
because diversity could be introduced at three different levels:
the indole, the aromatic ring of the imine, and the sulfonyl
group. It is important to highlight the remarkable robustness
shown by this specific resin: the same 360 mg batch of resin
was used for all the continuous-flow processes performed,
which include the 6 h operation experiment (Figure 4), the
compound library synthesis (Figure 5), as well as all the prelimi-
nary experiments devoted to parameter optimization.
Experimental Section
General procedure for the phosphoric acid catalyzed
Friedel–Crafts reaction
Conclusion
N-Sulfonylimine (0.07 mmol), indole (0.1 mmol), and resin
8
A very robust polystyrene-supported chiral phosphoric acid
catalyst has been developed. Its high applicability was success-
fully demonstrated in the Friedel–Crafts reaction of indoles
and sulfonylimines to afford the corresponding products with
high yields and enantioselectivities. Furthermore, this catalyst
(10 mol%) were placed in a vial and CH2Cl2 (0.44 mL, 0.16m) was
added. The reaction mixture was shaken until complete consump-
tion of the starting imine was detected by TLC. Then, the resin was
filtered and the filtrate was directly purified by column chromatog-
raphy on silica gel.
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Acknowledgements
We thank Dr. E. C. Escudero-Adan for performing the X-ray
analysis and for his invaluable help in obtaining the monocrys-
tal. Financial support by the MINECO (Grant CTQ2012-38594-
C02-01), AGAUR (Grant 2009SGR623), ICIQ Foundation, and the
EU-ITN network Mag(net)icFun (PITN-GA-2012-290248) is grate-
fully acknowledged. L.O.-P. thanks the MECD for an FPU fellow-
ship. C.R.-E. acknowledges the Generalitat de Catalunya for
a Beatriu de Pinꢃs B fellowship.
Keywords: asymmetric catalysis · chiral phosphoric acids ·
flow processes · Friedel–Crafts reactions · immobilization
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Received: October 2, 2013
Published online on January 23, 2014
Chem. Eur. J. 2014, 20, 2367 – 2372
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