Continuous flow enantioselective three-component anti -mannich reactions catalyzed by a polymer-supported threonine derivative

Article abstract of DOI:10.1021/cs5006037

A series of primary amino acid-derived polystyrene-supported organocatalysts was tested in anti-selective Mannich reactions. The polystyrene-immobilized threonine derivative showed the best performance in three-component (hydroxyacetone, anilines, and ald

Full text of DOI:10.1021/cs5006037

Research Article
pubs.acs.org/acscatalysis
Continuous Flow Enantioselective Three-Component anti-Mannich
Reactions Catalyzed by a Polymer-Supported Threonine Derivative
Carles Ayats,† Andrea H. Henseler,† Estefanía Dibello,† and Miquel A. Pericas*,†,‡
̀
†Institute of Chemical Research of Catalonia (ICIQ), Avda. Països Catalans, 16, E-43007 Tarragona, Spain
‡Departament de Química Organ
̀
ica, Universitat de Barcelona (UB), E-08028 Barcelona, Spain
S
* Supporting Information
ABSTRACT: A series of primary amino acid-derived
polystyrene-supported organocatalysts was tested in anti-
selective Mannich reactions. The polystyrene-immobilized
threonine derivative showed the best performance in three-
component (hydroxyacetone, anilines, and aldehydes) Man-
nich reactions to provide anti-β-amino-α-hydroxycarbonyl
compounds (11 examples; up to 95% ee), and its use could
be extended to dihydroxyacetone and protected hydroxyace-
tones (7 examples; up to 90% ee). The high activity depicted
by the catalyst has allowed its implementation in continuous flow. Under this operation mode, the supported threonine catalyst
produces anti-Mannich adducts with generally higher diastereo- and enantioselectivity than in batch. A family of five different
enantioenriched anti-Mannich adducts has been sequentially prepared in flow by passing different combinations of anilines and
aromatic aldehydes over the same sample of catalyst. This confirms the suitability of this methodology for the rapid access to
small libraries of enantioenriched compounds.
KEYWORDS: β-amino-α-hydroxycabonyl compounds, asymmetric catalysis, continuous flow, Mannich reaction, supported catalysts
tone to form adducts with a syn-1,2-amino alcohol
arrangement,5b,e with primary amino acids, the corresponding
anti adducts are formed.8b−l This is due to the fact that primary
amino acids mediate Mannich reactions via the (Z)-enamine
intermediate, this configurational preference results from an
extra hydrogen bonding interaction between the NH group and
the oxygen atom of the hydroxy group of the enamine.
Therefore, primary amino acid catalysis is complementary to
proline catalysis when hydroxyacetone and its O-protected
derivatives are used.8b,h
The high polarity of organocatalysts (e.g., free amino acids)
converts the isolation of similarly polar reaction products (e.g.,
Mannich adducts) into wasteful and tedious processes. A
successful strategy to overtake this problem is catalyst
immobilization onto solid supports, which allows catalyst
separation by simple filtration and the possibility of catalyst
recycling.14 In addition, properly designed, heterogenized
catalysts often replicate the properties of their homogeneous
analogues, with the advantage of being suitable for continuous
flow processes without coelution of the catalyst.5f,6d,15,16
Mannich reactions catalyzed by homogeneous primary amino
acid derivatives usually require high catalyst loadings (up to
30%);8a,b,e,f,i−k,9 thus, immobilization of these species appears
to be a very good alternative. In the literature, only two
examples of recyclable primary amino acid derivatives are
1. INTRODUCTION
The asymmetric Mannich reaction1 is one of the most versatile
methodologies for the preparation of valuable chiral amino
carbonyl compounds and their derivatives.2 In 2000, List
described the utility of L-proline as an excellent organocatalyst3
for three-component intermolecular asymmetric Mannich
reactions,4 and L-proline became a routine catalyst for this
transformation affording syn-products with high stereoselectiv-
ity.5 Although syn-Mannich products are readily accessible, anti-
Mannich products are more difficult to synthesize. Recently,
different organocatalysts have been found to catalyze Mannich
reactions to selectively achieve either syn- or anti-Mannich
products.2f,6 When α-hydroxyacetone and O-protected deriva-
tives are used as acyclic ketone donors in asymmetric Mannich-
type transformations, adducts with up to four adjacent
functional carbons featuring a central, stereodefined 1,2-
amino alcohol unit are obtained. These synthons are common
building blocks for the synthesis of complex α-amino acid
derivatives,5b,e as well as important precursors for different
types of bioactive compounds with high pharmaceutical value.7
The development of a simple and efficient way for the
preparation of these compounds in enantiomerically pure form
is thus of the utmost importance for synthetic organic
chemistry.
Natural primary amino acids and their derivatives have
recently caught attention as successful catalysts for different
asymmetric transformations such as Mannich,8,9 aldol,8b,e,k,10
Michael,11 α-amination,12 and cyanosilylation reactions.13
Although proline catalyzes Mannich reactions of hydroxyace-
Received: May 4, 2014
Revised: July 27, 2014
© XXXX American Chemical Society
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Research Article
reported to catalyze anti-Mannich reactions. One of them
involves a soluble catalyst and, therefore, extraction is required
before the catalyst can be reused.8m The other example reports
the use of a cysteine-derivative anchored onto magnetic
nanoparticles, however nonenantioenriched Mannich products
were obtained.17
Table 1. Evaluation of PS-Supported Primary Amino Acids
as Catalysts for the anti-Selective Mannich Reaction
a
We have recently reported on the use of polymer-supported
prolines and pyrrolidines as highly active and selective
heterogenized catalysts for Mannich reactions under batch
and continuous flow conditions leading respectively to syn-
products and anti-products, with excellent diastereo- and
enantioselectivities.5f,6d However, to the best of our knowledge
there are no examples of three-component enantioselective
anti-Mannich reactions catalyzed by supported organocatalysts.
Herein, we report the use of a polymer-supported threonine
derivative as a highly active and stereoselective catalyst for
three-component anti-Mannich reactions, and its use for the
implementation of a single pass, continuous flow process for
the preparation of a small library of anti-β-amino-α-
hydroxycarbonyl compounds in high enantiomeric purity.
b
b
c
entry
catalyst
time (h)
conv. (%)
syn/anti
ee (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
17
12
6
>99
>99
>99
>99
>99
>99
>99
>99
58:42
50:50
55:45
40:60
50:50
35:65
40:60
45:55
43
69
58
36
78
85
73
80
3
6
6
d
6
8
e
6
8
a
Reactions were performed with catalyst 1−6 (20 mol %), preformed
imine 7 (0.125 mmol), and hydroxyacetone (6 equiv) in DMF (0.25
b
c
mL). By 1H NMR of the crude mixture. anti-Isomer; by chiral
d
e
2. RESULTS AND DISCUSSION
HPLC after purification. 10 mol % of 6 was used. 15 mol % of 6 was
used.
We have recently reported the preparation of a series of
polymer-supported primary amino acid derivatives 1−6 (Figure
1) and their use as heterogeneous catalysts for aldol
enantioselectivity (entry 4). In turn, catalyst 5 derived from
5-hydroxytryptophan afforded product 8 with high levels of
enantioselectivity but in poor diastereoselectivity (entry 5).
Threonine derivatives have been reported to display very
good catalytic activity for enantioselective anti-Mannich
reactions.8b−f,i−k Very gratifyingly, the supported threonine 6
also displayed this behavior and showed the best catalytic
performance (entry 6) in terms of both diastereo- and
enantioselectivity.
Once 6 was selected as the optimal catalyst, the effect of the
solvent nature on the performance of the reaction was studied
(Table 2). With DMF, no difference was observed regarding
either catalytic activity or selectivity when reagent grade or
anhydrous solvent was used (entries 1 and 2). In both cases,
reaction rates were low, although good stereoselectivities were
achieved. Using THF stereoselectivity was not improved, but a
shorter reaction time was required (entry 3). Despite the fact
that some examples of anti-selective Mannich reactions
catalyzed by primary amino acid derivatives using NMP (N-
methyl-2-pyrrolidone) have been described,8b,f,i−k in the
presence of catalyst 6, a slow reaction took place, and the
product was obtained with low enantioselectivity (entry 4).
Conversely, the reaction showed to be very fast when CH2Cl2,
toluene, or solvent-free conditions were tested; unfortunately,
only moderate to very poor enantioselectivities were achieved
in these cases (entries 5, 6 and 7). On the other hand, the
presence of water as a cosolvent exclusively led to the
decomposition of imine 7 (entry 8).5f In light of these results,
we tested different mixtures of DMF (better results regarding
stereoselectivity) and CH2Cl2 (better results regarding reaction
rate and swelling ability for Merrifield-derived resins) (entries
9, 10, and 11). Gratifyingly, a 1:1 mixture of DMF and CH2Cl2
led to a significantly improved yield as well as to excellent
enantioselectivity (Table 2, entry 10). As a consequence of the
hydrolytic instability of imine 7, optimal reaction conditions
involved performing the reaction in the glovebox with
anhydrous solvents (entry 12) and in the presence of molecular
sieves (entry 13). In this way, the Mannich adduct 8 could be
obtained in very short reaction time (1 h) and with good
Figure 1. Primary amino acid-derived catalysts.
reactions.10j Among them, catalyst 6 showed the best catalytic
performance regarding activity and stereoselectivity, yielding
aldol products of high enantiopurity.
With these catalysts in hand, we proceeded to evaluate them
in Mannich reactions, using hydroxyacetone and preformed N-
(p-methoxyphenyl) (N-PMP) ethyl glyoxylate imine 7 as the
benchmark process (Table 1). DMF was used as the solvent for
this transformation due to both its good swelling ability for
polymer-supported organocatalysts and previous experience in
the laboratory.5f,6d
Polystyrene-supported cysteine and serine derivatives 1 and
2 catalyzed the formation of compound 8 but showed only low
activity (entries 1 and 2). Moreover, in the case of cysteine
derivative 1, the syn-Mannich product was obtained as the
major diastereomer.18 Catalyst 4 was synthesized as a
promising potential catalyst due to its close structural similarity
with immobilized trans-4-azidoproline.5f Although this species
did not show catalytic activity for aldol reactions,10j it mediated
the formation of anti-Mannich product 8 in a remarkably short
reaction time (3 h), albeit with disappointingly low
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a
Table 2. Solvent Screening for the Mannich Reaction between Hydroxyacetone and Preformed Imine 7 Catalyzed by Resin 6
b
c
d
entry
solvent
time (h)
yield (%)
syn/anti
ee (%)
e
1
2
DMF
6
5
35
35
37
16
53
46
51
−
42
52
45
56
58
35:65
37:63
50:50
59:41
64:36
65:35
63:37
−
36:64
26:74
41:59
26:74
21:79
85
84
74
33
66
0
anhyd DMF
anhyd THF
NMP
3
3
4
6
5
anhyd CH2Cl2
neat
1,5
0,5
1
6
7
anhyd toluene
60
8
DMF/H20 (80:20)
7
−
e
e
e
9
DMF/CH2Cl2 (80:20)
DMF/CH2Cl2 (50:50)
DMF/CH2Cl2 (20:80)
3
85
93
88
94
96
10
11
2
2
f
12
anhyd DMF/anhyd CH2Cl2 (50:50)
anhyd DMF/anhyd CH2Cl2 (50:50)
1,5
1
f g
13 ,
a
Unless otherwise stated, the reactions were performed with catalyst 6 (20 mol %), preformed imine 7 (0.125 mmol) and hydroxyacetone (6 equiv)
b
c
d
e
1
in 0.25 mL of solvent. Isolated product. By H NMR of the crude mixture. anti-Isomer; by chiral HPLC after purification. Synthesis grade
solvents were used. Reaction performed in the glovebox. 4 Å molecular sieves were used.
f
g
a
Table 3. Scope of the Reaction of Hydroxyacetone with Different Amines and Aldehydes Catalyzed by Resin 6
b
c
d
entry
R1
R2
product
time (h)
yield (%)
syn/anti
ee (%)
1
2
H
H
H
9
6
5
7
4
8
4
5
8
8
5
3
96
88
90
89
62
84
86
72
70
87
88
8:92
9:91
93
92
82
85
49
81
83
67
83
87
95
p-NO2
H
10
11
12
13
14
15
16
17
18
19
3
p-CH3O
p-CH3O
p-CH3O
p-CH3O
p-CH3O
p-CH3O
p-CH3O
p-CH3
28:72
13:87
52:48
22:78
19:81
37:63
15:85
11:89
12:88
4
p-NO2
p-CH3O
p-Br
5
6
7
p-CN
p-Cl
8
9
o-Cl
10
11
p-NO2
p-NO2
p-Cl
a
Reactions were performed with catalyst 6 (20 mol %), amine (0.2 mmol), aldehyde (1.1 equiv), and hydroxyacetone (6 equiv) in 1:1 DMF/CH2Cl2
b
c
d
1
(0.4 mL). Isolated product. By H NMR of the crude mixture. anti-Isomer; by chiral HPLC after purification.
diastereoselectivity (syn/anti = 21:79) and excellent enantiose-
lectivity (96% ee).
adducts 9−19 in moderate to good diastereo- (up to 8:92) and
enantioselectivities (up to 95% ee), with yields up to 96%.
When the reaction was carried out with an aldehyde bearing an
electron-donating substituent in para position (entry 5), poor
enantioselectivity was observed as previously reported in the
literature.8b It is worth noting that the present procedure
affords anti-Mannich products in good enantioselectivities
when performing the reactions at room temperature, whereas
most of the reported anti-Mannich reactions with hydrox-
yacetone catalyzed by primary amino acid derivatives require
low temperatures for the achievement of high enantioselecti-
vities.8b,i−k
Once the reaction conditions were optimized, the next step
was to explore the scope of the anti-Mannich reactions of
hydroxyacetone with different amines and aldehydes (Table 3).
To avoid possible problems arising from hydrolytic instability
of the intermediate imines, the possibility of performing the
reactions as “one-pot”, three component processes was
explored. Interestingly, the reactions took place under these
conditions without the need for special precautions.
The results show that three-component anti-Mannich
reactions mediated by 6 can be completed in 3−8 h using
unsubstituted aniline (entries 1−2) and p-substituted (me-
thoxy, methyl, chloro) derivatives (entries 3−11), yielding anti-
The scope of the asymmetric, anti-selective Mannich reaction
mediated by 6 could be further expanded (Table 4) with the
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a
Table 4. Scope of the Reaction Using Different Ketone Donors
b
c
d
entry
R1
R2
R3
product
time (h)
yield (%)
syn/anti
ee (%)
e
e
1
2
3
4
5
6
7
OH
OH
H
p-BrC6H4
p-CNC6H4
p-NO2C6H4
p-CNC6H4
2,4-Cl2C6H3
i-Bu
20
21
22
23
24
25
26
8
74
76
94
80
84
52
77
34:66
29:71
23:77
25:75
12:88
47:53
67:33
67
82
80
90
77
82
H
8
H
H
H
H
H
Bn
Bn
Bn
Bn
TBS
38
36
38
22
24
f
p-NO2C6H4
51
a
Reactions were performed with 6 (20 mol %), p-anisidine (0.2 mmol), aldehyde (1.1 equiv), and ketone (6 equiv) in a 1:1 mixture of DMF/
b
c
d
e
CH2Cl2 (0.4 mL). Isolated product. By 1H NMR of the crude mixture. anti-Isomer; by chiral HPLC after purification. Dihydroxyacetone dimer
(3 equiv) and acetic acid (10 mol %) were used. anti-Isomer; by chiral HPLC of the desilylated product.
f
use of additional ketones, including 1,3-dihydroxyacetone
(entries 1 and 2), protected hydroxyacetones (entries 3−7),
aromatic and aliphatic aldehydes, and p-anisidine.
Table 5. Recycling Experiments for the Reaction between
the α-Hydroxyacetone, Aniline, and p-Nitrobenzaldehyde
a
Notably, resin 6 catalyzed the three-component anti-
Mannich reactions of dihydroxyacetone19 affording anti-
dihydroxy-β-aminoketones 20 and 21 (entries 1 and 2).
These densely functionalized compounds are of high synthetic
importance for the preparation of amino sugars.20 Despite only
moderate stereoselectivities (up to 82% ee), these results are
among the best previously reported for the same trans-
formation.8f In the case of O-benzylhydroxyacetone, we studied
this transformation with both electron-deficient aromatic
aldehydes (entries 3, 4, and 5) and aliphatic aldehydes (entry
6), leading to the formation of the orthogonally protected β-
amino-α-hydroxyketones 22−25. In these cases, the reactions
were slower but took place with high enantioselectivity.
Notably, when the reaction was performed with TBS-protected
α-hydroxyacetone, the diastereoselectivity of the process could
be reversed, with the syn-Mannich adduct being obtained as the
major product, and poor enantiomeric excess of the anti-isomer
was recorded (Table 4, entry 7).8d
b
b
c
run
conv. (%)
syn/anti
ee (%)
1
2
3
4
>99
>99
>99
82
9:91
10:90
10:90
17:83
28:72
92
92
89
55
67
d
5
25
a
Reactions were performed with catalyst 6 (20 mol %), aniline (0.2
mmol), p-nitrobenzaldehyde (1.1 equiv), and hydroxyacetone (6
equiv) in a 1:1 mixture of DMF/CH2Cl2 (0.4 mL). By H NMR of
the crude mixture. anti-Isomer; by chiral HPLC after purification.
After washing with acetic acid (10%) in a 1:1 mixture of DMF/
b
1
c
d
CH2Cl2.
To exploit one of the advantages offered by catalyst
immobilization, we explored the recyclability of PS-supported
threonine 6 in the Mannich reaction between α-hydroxy-
acetone, aniline, and p-nitrobenzaldehyde to afford anti-β-
amino-α-hydroxyketone 10 (Table 5). After each run, the
catalyst was recovered by simple filtration and directly used in
the next cycle. Working under the specified reaction conditions,
a decrease in the activity and selectivity of the catalyst was
observed after the third cycle in a highly reproducible manner.
Starting from the preformed imine (see Supporting Informa-
tion) or performing the recycling in the glovebox entailed no
improvement of these results. Attempts to reactivate the resin
by washing with AcOH also proved unsuccessful (entry 5). To
understand the origin of the deactivation process, the initial and
the deactivated resins were studied by elemental analysis and by
IR spectroscopy (see Supporting Information). No change in
the functionalization level (% N) was observed, suggesting that
no cleavage of the monomer has taken place. On the other
hand, the IR spectrum shows an almost complete disappear-
ance of the carboxylate bands and the appearance of a weak
absorption at 1715 cm−1, suggesting that the excess of
hydroxyacetone required for the reaction to proceed, slowly
reacts with the supported amino acid leading to some
catalytically less active and less stereoselective derivative. In
any case, the recycling process allows achieving an accumulated
TON > 20, which compares very favorably with the values (3−
5) achieved with the reference homogeneous catalysts.8b
In view of the results obtained with immobilized catalyst 6
under batch conditions, we envisaged the possibility of
performing the asymmetric, three-component Mannich reac-
tion in continuous flow. The experimental setup for the flow
synthesis of compound 10 is represented schematically in
Figure 2 (see Supporting Information for more details). It
consisted of a vertically mounted and fritted, volume-adjustable
low-pressure glass chromatography column loaded with the
polymer-supported catalyst 6. The reactor inlet was connected
to a T-shaped adaptor, which allows switching between two
channels, connected to two syringe pumps. One channel was
connected to a solution with the three reactants (no reaction
occurs in absence of catalyst) in a 1:1 mixture of DMF/CH2Cl2,
and the other channel was connected to a flask containing the
same solvent mixture, to rinse the system. Continuous inline IR
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Figure 2. Experimental setup for the continuous flow experiments.
Scheme 1. Continuous Production of anti-Mannich Products 10 and 19
analysis was used to determine the optimal flow rate for
complete conversion.21
Mannich adducts in a sequential manner. This is a rather
unique application of flow processes with immobilized catalytic
systems and allows the preparation of focused libraries of drug
candidates or drug intermediates with important advantages.
Thus, the products are obtained free of contamination by the
catalyst, and the scale of production can be simply controlled
through the operation time.6c,16c,f,g Furthermore, these
sequential processes are easily amenable to automation. Thus,
by operating the same continuous flow setup described above, a
single sample of catalytic resin 6 could be used to prepare five
different anti-Mannich compounds in a sequential process. In
this event, the flow preparation of every adduct was run for 1 h
(flow rate of 30 μL·min−1), and the operation only involved
washing the resin by circulation of a 1:1 mixture of DMF/
CH2Cl2 for 30 min between two different substrates. The
results obtained in the preparation of this sequential library are
summarized in Scheme 2.
Thus, a solution of aniline, hydroxyacetone, and p-nitro-
benzaldehyde was pumped through a column loaded with 300
mg of catalyst 6 (f = 1.02 mmol·g−1) with a flow rate of 30 μL·
min−1 (corresponding to 17 min residence time) (Scheme
1a).22 The system was operated for 6 h producing 3.13 mmol of
10, with diastereo- and enantioselectivity very close to those
recorded under batch conditions (Table 3, entry 2).23 Likewise,
after pumping for 4 h, a solution of p-chloroaniline,
hydroxyacetone, and p-nitrobenzaldehyde,24 2.78 mmol of
highly enantioenriched anti-Mannich adduct 19 was obtained
(Scheme 1b).25 In this case, slightly better diastereo- and
enantioselectivity was recorded with respect to the correspond-
ing batch process (Table 3, entry 11). Remarkably, both
continuous flow processes allow for a 2-fold reduction of the
catalyst amount compared to the batch processes mediated by
resin 6.26
The five target anti-Mannich adducts 9, 12, 15, 18, and 19
were obtained in good yields and in high diastereo- and
enantiomeric purities. Remarkably 9, 12, and 19 were obtained
in this manner with slightly better stereoselectivities than under
batch conditions (see Table 3, entries 1, 4, and 11). High
The successful use of resin 6 in continuous flow conditions,
together with the importance of the resulting enantioenriched
Mannich adducts as advanced synthons for the preparation of
biologically active compounds,7 prompted us to explore the
possibility of preparing a small library of enantioenriched anti-
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combined liquid phases were concentrated under reduced
pressure. Purification by column chromatography (eluting with
cyclohexane/AcOEt) gave the corresponding Mannich prod-
ucts 9−26. Conversion and diastereomeric ratio were
Scheme 2. Continuous Flow Production of a Library of
Enantioenriched anti-Mannich Adducts
a
1
determined by H NMR of the crude samples after removal
of the resin. The enantiomeric excess was determined by HPLC
on a chiral stationary phase after purification by column
chromatography. In the recycling experiments, the dried resin
was used in the next run without further treatment.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: mapericas@iciq.es. Fax: (+34)977-920-244. Tel.:
(+34)977-920-243.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by MINECO (grant CTQ2012-38594-
C02-01), DEC (grant 2014SGR827), and ICIQ Foundation.
We also thank MINECO for support through Severo Ochoa
Excellence Accreditation 2014−2018 (SEV-2013-0319). C A.
thanks MICINN for a Juan de la Cierva postdoctoral
fellowship. A.H.H. thanks the MECD for an FPU fellowship.
E.D. thanks to ANII, CSIC Uruguay and PEDECIBA for
financial support.
a
Productivities in mmolproduct·mmolresin−1·h−1are shown in parentheses.
REFERENCES
(1) Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647−667.
■
productivities were recorded with all tested substrates, ranging
̈
from 1.6−2.1 mmolproduct·mmolresin−1·h−1.
(2) For reviews see: (a) Arend, M.; Westermann, B.; Risch, N. Angew.
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J.-C. In Comprehensive Asymmetric Catalysis, Vol. II; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; pp 923−
961. (c) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069−1094.
3. CONCLUSIONS
In summary, we have identified a threonine derivative
immobilized onto polystyrene through a 1,4-disubstituted
1,2,3-triazole linker (6) as an efficient organocatalyst for the
three-component anti-Mannich reaction. The immobilized
catalyst depicts high activity and stereoselectivity in dichloro-
methane−N,N-dimethylformamide mixtures and allows recy-
cling and reuse (three cycles). The good overall performance of
6 allowed adapting its use to single-pass, continuous flow
processes. We have also shown that this flow system can be
applied to the diastereo- and enantioselective medium-scale
preparation of a diverse library of anti-Mannich adducts in a
sequential manner. Noteworthy, these are the first examples of
anti-selective, three component asymmetric Mannich reactions
performed in continuous flow.
́ ́
(d) Cordova, A. Acc. Chem. Res. 2004, 37, 102−112. (e) Arrayas, R. G.;
Carretero, J. C. Chem. Soc. Rev. 2009, 38, 1940−1948. (f) Cai, X.-H.;
Xie, B. Arkivoc 2013, 264−293 and references herein.
(3) (a) de Meijere, A.; Diederich, F. In Asymmetric Organocatalysis;
Berkessel, A., Groger, H., Eds.; Wiley-VCH: Weinheim, 2005; pp
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104−106. (b) Tanaka, F.; Barbas III, C. F. In Enantioselective
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4. EXPERIMENTAL DETAILS
General Procedure for the Asymmetric Multicompo-
nent Mannich reaction. Polymer-supported catalyst 6 (20
mol %) was swollen in a vial with a 1:1 mixture of DMF/
CH2Cl2 (0.4 mL). The amine (0.2 mmol), aldehyde (1.1
equiv), and ketone (6 or 3 equiv of dihydroxyacetone dimer
plus 10 mol % acetic acid) reactants were added, and the
reaction mixture was shaken at room temperature for the times
indicated in Tables 3 and 4. Then, the resin was filtered off,
washed with AcOEt (3 × 1 mL), and dried under vacuum. The
̀
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̀
,
(23) The use of continuous flow conditions for 6 hours results in a
turnover number (TON) of 10 (referred to the product formed) and a
productivity of 1.7 mmolproduct·mmolresin−1·h−1.
(24) A flow rate of 50 μL·min−1 was used (equivalent to 10 min
residence time).
(25) The use of continuous flow conditions results a turnover
number (TON) of 9 (referred to the product formed) and a
productivity of 2.2 mmolproduct·mmolresin−1·h−1.
(26) The turnover number (TON) for the synthesis of compounds
10 and 19 under batch conditions was 4.5 (referred to the product
formed).
(15) For recent examples, see: (a) Kirschning, A.; Jas, G. In
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3033
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