This is the peer reviewed version of the following article React. Chem. Eng., 2018,3, 714-721, which has been published in final form
https://doi.org/10.1039/C8RE00101D .

A versatile, immobilized gold catalyst for the reductive amination of aldehydes in
batch and flow
a

a

a,b,*

Adela I. Carrillo, Patricia Llanes and Miquel A. Pericàs

An efficient and environmentally friendly catalytic route for the reductive amination of carbonyl compounds has been designed. First, a one-pot procedure
has been followed for the synthesis and incorporation of gold nanoparticles (AuNPs) into a mesoporous silica solid by using light as an abundant and clean
energy source. Then, the as-prepared material has been successfully employed as an heterogeneous catalyst in the production of secondary and tertiary
amines by reductive amination using Ph(Me)2SiH as the reducing agent. The endurance of the catalyst has been demonstrated in batch, and a continuous
flow process allowing the safe preparation of multigram amounts of reductive amination products (accumulated TON = 434 in 18 h operation involving 6
sequential examples) has been implemented. The scope of the reaction has also been extended to the synthesis of more challenging active pharmaceutical
ingredients (APIs), such as indoprofen precursors and biomass-derived products, which were obtained in good to excellent yields.

Introduction
Due to the ubiquity of amines among natural products, and the
prevalence of amino groups in the molecules of synthetic
intermediates, pharmaceutical ingredients and fine chemicals, the
1
efficient, economical and environmentally friendly synthesis of
amines is nowadays a very active field in preparative organic
1
chemistry. Strategies involving C-N bond formation are generally
used to introduce the desired amine functionalities into organic
2
3
compounds. Although various methods are known, the broad
availability and low cost of starting materials such as aldehydes,
ketones and amines make the direct reductive amination of
carbonyl compounds one of the most practical and efficient
approaches to the preparation of complex amines. From a practical
perspective, one-pot processes allowing the initial imine formation
in the presence of the reducing agent are the subject of current
4
interest. In this context, silanes containing Si-H bonds have
appeared as a competitive, green alternative for the production of
4c,5
fine chemicals through mild and selective reduction processes.
Looking for a more sustainable approach to produce amine-based
fine chemicals, the use of biomass as feedstocks has appeared as a
plausible route due to the vast availability of lignocellulosic
6
materials. In this respect, the utilization of 5-hydroxymethylfurfural
(HFM) or levulinic acid derived from lignocellulosic biomass have
arisen as green platform molecules to synthesize aminoalkylfuran
derivatives, or lactams skeletons, which are key building blocks in
7
many biologically active natural products.
The use of transition metal nanoparticles as catalysts for a variety of
organic transformations has witnessed a dramatic growth in recent
8
times. Various transition metal nanocatalysts have proven their
9
value in the reductive amination of carbonyl compounds. Among
them, gold nanoparticles (AuNPs) have attracted significant
attention due to their unique reactivity, leading to the promotion of
10
reactions under mild conditions.
Traditional methods to
synthesize supported AuNPs include co-precipitation, depositionprecipitation, ion-exchange, impregnation and successive reduction
11
and calcinations. These procedures, however, present some
notorious drawbacks, such as the lack of control over nanoparticle
size or morphology, and the occurrence of metal leaching from the
as-prepared nanoparticles during the catalytic process. Thus, the
development of straightforward routes to support gold
nanoparticles leading to non-leachable materials presents a
remarkable interest. Scaiano and coworkers reported a

photochemical synthesis of stable, unprotected AuNPs by using
12
Irgacure 2959 as a photosensitizer. Later on, the same research
group designed a new synthetic route to efficiently prepare AuNPs
supported onto nanostructured silica MCM-41 through a one-pot
approach where nanoparticles were synthesized and immobilized
by using light as a cheap and abundant energy source. The assynthesized materials were successfully used as molecular delivery
13
systems.
Even though the combination of heterogeneous gold nanocatalysts
with microreactor technology offers various advantages when
14
15
compared to batch processes, research on this topic is scarce.
Besides the inherent process intensification (continuous product
formation and catalyst separation) associated to this approach,
other advantages include minimized waste production, intrinsically
high safety, easy handling of reactants, use of the same catalyst
samples for extended periods of time (resulting in high TONs), and
the possibility of operating reactions under harsh conditions with
16
simultaneous avoidance of by-product formation.
14
In this work, we report a highly efficient approach for the
synthesis of gold nanoparticles supported onto mesoporous silica
SBA-15 and the catalytic use of this hybrid material for the
reductive amination of carbonyl compounds leading to secondary
and tertiary amines in batch and flow. Lignocellulosic biomassderived aldehydes can be used for the efficient and green
preparation of high added-value aminoalkylfurans and lactams
17
through this process.

Results and discussion
Preparation of Au@APTES@SBA
The catalyst was prepared as shown in Scheme 1. Gold
nanoparticles (AuNPs) were synthesized and immobilized onto the
mesoporous silica by following a one-pot procedure. Firstly, SBA-15
18
silica was prepared by a conventional sol-gel approach. This
mesoporous solid was refluxed with 3-aminopropyltriethoxysilane
in toluene to afford the hybrid amine-based APTES@SBA (2), and
the resulting material was added to an aqueous mixture of the gold
precursor together with the photosensitizer Irgacure 2959. Then,
the yellow solution was placed into a photoreactor and irradiated
13
with 16 mid-range (300 nm) UV lamps for 30 min.

H2O + HCl +

H

O

O

xO

Si (OEt)3

a) 2h, 40 ºC
b) C8H20O4Si,
40ºC, 24 h

y

z

OH

Reflux, 16 h

c) 100ºC, 48 h,
calcination

= H2N
1
SBA-15
Mesoporous silica

hn

O
OH
+
HO

Si
O
O

Si
OH

O

2
APTES@SBA
Mesoporous silica

O

Si
O

HO
O

O
3
Irgacure-2959

OH OH

16 lamps
(300 nm)

HAuCl4. 3 H2O
30 min

AuNPs
4
Au@APTES@SBA
Mesoporous silica

Scheme 1 Schematic illustration of the synthesis of the hybrid
catalyst Au@APTES@SBA (4).
Characterization of hybrid Au nanoparticles functionalized
mesoporous silica
Firstly, the morphology and structural features of the material were
studied by using microscopy techniques (Figure 1). Gold metal is
clearly present in the silica as spherical nanoparticles in the size
range of 8-15 nm [Figure 1 (b) and (c); average size of 8.4 nm] as
shown by TEM. This technique also reveals that the incorporation of
AuNPs did not disturb the mesoporous structure of SBA-15, as
further confirmed by the X-ray diffraction (XRD) pattern (Figure 2).
Indeed, the typical nanochannels of this kind of mesoporous
materials are observed in both the pristine SBA-15 silica and in the
Au@APTES@SBA synthesized solid [Figure 1 (a) and (c)]. Moreover,
mapping spectroscopy revealed the good dispersion of the
nanoparticles on the silica matrix [Figure 1 (d)].
Figure 2 shows the low-angle XRD patterns of the mesoporous
materials. As it can be observed in the figure, three well-resolved
diffraction peaks are present for the three silica types: a very
o
intense peak around 2 = 1.2 and two weak peaks at the 2 range
o
o
between 1.5 and 2.0 , attributed to the (100), (110) and (200)
19
planes, respectively, thus demonstrating that there is no
alteration in the ordered two-dimensional hexagonal porous
structure of the solids during the synthesis of the hybrid catalyst.

Figure 1 TEM images of the (a) pristine SBA-15 and (b and c)
Au@APTES@SBA material. (d) TEM elemental mapping of the Au
M-edge signals.

Figure 2 Low-angle XRD patterns of the mesoporous silica materials.
The nitrogen adsorption-desorption isotherms and the
corresponding pore size distribution of the as-synthesized catalyst
are presented in Figure 3. For comparison purposes, the isotherms
of the initial SBA-15 and of the APTES@SBA silica are also included.
All solids exhibited type IV isotherms with a distinctive nitrogen
uptake at the relative pressure of 0.55 < P/P0 < 0.85, which is
characteristic of materials possessing regular cylindrical mesopores
20
with a narrow pore-size distribution. Based on the isotherms,
textural parameters were calculated and listed in Table 1. As
expected, both the pore diameter and the surface area decreased
after the incorporation of the AuNPs into the mesopores, probably
as a result of partial blocking of the porosity in the hybrid material.
Besides textural parameters, Table 1 shows the metal loading of the
hybrid catalyst 4 material as well as the content of the organic
moiety (APTES) used to anchor the AuNPs onto the silica matrix
(measured as nitrogen % weight). Notably, all of the gold presumed
to be anchored onto the silica material was successfully
immobilized, precious waste being completely avoided in this step.

Fig. 3 Nitrogen adsorption/desorption isotherms at 77 K (left) and their corresponding pore size distribution (right) of the mesoporous
silicas.
Table 1 Textural properties of SBA-15 and Au@APTES@SBA.
dp (nm)

a

2

-1 b

2

-1 c

-1 d

SBET (m g )

Vp (cm g )

Amount of N (mmol g )

Metal loading (wt %)

SBA-15

6.3

728.8

0.9

–

–

Au@APTES@SBA

5.8

425.4

0.6

1.5

e

3.0

a

Average mesopore diameters were estimated from the desorption branch of the nitrogen isotherm using the BJH method. bThe BET surface area was
estimated by multipoint BET method using the adsorption data in the relative pressure (P/P0) range of 0.05–0.30. cMesopore volume from the isotherms at
the relative pressure of 0.8. d Amount of N based on EA. e Gold amount determined by ICP analysis.

Catalytic activity
The catalytic performance of Au@APTES@SBA on the model
reaction of benzaldehyde (5a) and aniline (6a) was first evaluated in
different solvents (see Supporting Information Table S1). For this
study, we tentatively selected the optimal reaction conditions for
the reductive amination of aldehydes already described in the
21
literature, (1 h reaction time at room temperature under Ar with
1.5 equiv. of reducing agent [Ph(Me)2SiH] and 0.5 mol % of the gold
catalyst). In agreement with recent reports, toluene appeared as
4e,7b,22
the optimal solvent for the studied reaction.
Nevertheless,
high yields were also obtained when the reaction was performed in
more environmentally friendly solvents such as methanol or
isopropanol (Table S1, entries 3 and 4). Notably, no reaction was
observed in the absence of the Au@APTES@SBA catalyst (Table S1,
entry 1). Taking into account compatibility with the catalytic
material (see below) and safer use , isopropanol was chosen as the
best solvent to perform the reductive amination. In practice, the
combined use of a benign solvent such as isopropanol with 1 mol %
Au@APTES@SBA led to high yields of the target amines.
Interestingly, ICP analysis of reaction crudes resulting from these
conditions revealed the absence of gold above the lower detection
limit (10 ppm), thus confirming the stability of the Au@APTES@SBA
catalyst.
The scope of the reductive amination reactions catalysed by
Au@APTES@SBA was next evaluated under the optimized reaction
conditions (Supporting Information: Table S1, entry 5). We started
by studying the effect of substitution on the aromatic system of the
benzaldehyde reactant (Table 2). The reaction proceeded smoothly
with benzaldehydes containing meta and para electron-donating
(5b, 5c, 5e) and weakly electron-withdrawing (5d, 5f) groups,
affording the corresponding amines 7 in good to excellent yields
21
within 2 h at room temperature. The methodology was also found

to be applicable to heterocyclic aldehydes. Thus, furfural (5g)
provided the secondary amine 7ga in 76% yield. Reaction with
bulkier aromatic aldehydes such as 2-naphtaldehyde (5h) was
sluggish and required extended reaction times (14 h), higher
temperatures and catalyst loading (60 ºC, 2 mol %), although the
corresponding amine (7h) was produced in high yield (79 %). The
reductive amination of -unsaturated 3-methylbut-2-enal (5i)
took also place in a satisfactory manner, amine 7ia being also
obtained in high yield (80%) after 14 h at 60 ºC. No hydrogenation
of the C=C group was observed in this process. Unfortunately, the
reaction did not work with aliphatic aldehydes like heptanal (5j),
very low conversion being observed in isopropanol after 14 h at 60
ºC.
The influence of the amine counterpart on the reaction outcome
was also investigated. Electron-rich toluidines (6b-c) and electrondeficient para-bromoaniline (6d) afforded the corresponding
amines 7ab-7ad in good yields after 14 h at 60 ºC. When an
electron-rich but rather hindered aniline was used (2,4dimethoxyaniline, 6e), a slow reaction was observed at room
temperature. However, when the reaction was performed at 60 ºC,
a 61% yield of 7ae was achieved after 24 h. Morpholine (6f),
featuring a secondary amino group, also worked well when reacted
with benzaldehyde, affording amine 7af in 70 % yield. On the other
hand, the reaction of benzaldehyde with a primary aliphatic amine
(butylamine, 6g) afforded amine 7ag in a moderate 55 % yield
under the standard reaction conditions, this being consistent with
23
previous results. Finally, when the reaction of benzaldehyde with
ammonia in methanol was attempted no benzylamine could be
isolated from the reaction crudes in spite of extensive
experimentation.

Table 2 Reductive amination of aldehydes with amines over
a
Au@APTES@SBA hybrid catalyst.

R1

CHO

Au@APTES@SBA
4 (1 mol%)

R2
HN
R3

+

5a-5i

R1

R3

Ph(Me)2SiH, IPA

amine
7xy

6a-6h

Aldehyde1

R1

5a
5b
5c
5d
5e
5f
5g
5h
5i
5j

phenyl
4-methylphenyl
4-methoxyphenyl
4-bromophenyl
3-methylphenyl
3-bromophenyl
2-furyl
2-naphthyl
2,2-dimethylvinyl
hexyl

R2

N

Amine1

aldehyde

R2

R3

H
6a
phenyl
H
6b
4-methylphenyl
H
6c
4-methoxyphenyl
H
6d
4-bromophenyl
6e 2,4-dimethoxyphenyl H
-CH2CH2OCH2CH26f
H
6g
butyl
H
6h
H

N
H

N
H

N
H
MeO

7aa: 1 h, rt, 90% yield

7ba: 2 h, rt, 94% yield

Br

N
H

N
H

7ca: 2 h, rt, 76% yield

N
H

Br
7da: 2 h, rt, 76% yield

7ea: 2 h, rt, 77% yield

N
H

O

7fa: 2 h, rt, 77% yield

N
H

7ga: 2 h, rt, 76% yield

N
H

7ha:b,c 14 h, 60 ºC, 79% yield

7ia: 14 h, 60 ºC, 80% yield
OMe

N
H

5 N
H
7ja: 14 h, 60 ºC, 0% yield

N
H

7ab: 14 h, 60 ºC, 81% yield

Br

MeO

N
H

7ac: 14 h, 60 ºC, 84% yield

OMe
N

N
H

7ad: 14 h, 60 ºC, 80% yield

O

7ae:d 24 h, 60 ºC, 61% yield
N
H

7ag, 55% yield, 14 h, 60 ºC

7af: 14 h, 60 ºC, 70% yield
NH2

7ah:e 24 h, rt, 0% yield

a

Reaction conditions: 5 (0.5 mmol), 6 (0.5 mmol),dimethylphenylsilane (0.75
mmol), isopropyl alcohol (1 mL) and Au@APTES@SBA catalyst (1 mol%).
Yields correspond to isolated products. bReaction performed at 0.3 mmol
scale. c2 mol% of Au@APTES@SBA was used. dConversion after 24 h at rt
was 33%. eThe reaction was performed in MeOH. 10 eq. of NH3/MeOH were
used.

The versatility of the Au@APTES@SBA catalyst could also be
demonstrated in the synthesis of isoindolinones, a structural type
7b
found in many important biologically active compounds. Both
electron-donating (OMe and Me) and –withdrawing (Br) groups on
the aromatic substituents of amines were tolerated, the target
isoindolinones 9a-d being obtained in 80-90% yields (Scheme 2a).
Finally, the activity of the gold catalyst was tested on the synthesis
of high added-value, biomass-derived compounds (in addition to
7ga) from levulinic acid and 5-hydroxymethylfurfural (Scheme 2b-

24,25

c).
To our delight, Au@APTES@SBA provided good yield of 11
(75%) within 14 h at 60 ºC, which compares favourably to the
7,25,26
heterogeneous catalysts reported so far for such reaction.
Moreover, and in contrast to other reported supported
25,27
catalysts,
our hybrid material performed the reductive
amination of 5-hydroxymethylfurfural under very mild conditions,
giving the desired product (13) in 65% yield within 14 h at 60 ºC.
Encouraged by the catalytic performance and versatility of the
Au@APTES@SBA catalyst, we wanted to demonstrate its viability
for preparative purposes by scaling-up the preparation of some of
the reductive amination products to gram quantities under flow
conditions. With this purpose, the two-pump system outlined in
Table 3 was assembled. As depicted, a packed bed reactor
containing Au@APTES@SBA was fed with two solutions containing,
in one case, the selected aldehyde and the corresponding amine
and, in the other case, dimethylphenylsilane as the reducing agent.
Preliminary evaluation and optimization studies were conducted
using a flow microreactor where isopropanol solutions of
benzaldehyde and aniline (0.41 M each) and dimethylphenylsilane
(0.62 M) were simultaneously pumped through a cartridge reactor
packed with 0.500 g of Au@APTES@SBA (0.076 mmol Au) with
precise control of the flow rates. The exiting product stream was
1
collected, concentrated under vacuum and analysed by H NMR
spectroscopy to determine conversion and selectivity. High yields,
comparable to those already obtained in the batch reaction were
−1
achieved for flow rate ≤ 200 μL min . Since a further increase in
−1
flow rate to 250 μL min resulted in lower conversion, a flow rate
−1
of 200 μL min was selected as the optimal one and used to explore
the scope of the reaction in flow.
With the optimized conditions in hand the substrate range was
extended to a variety of benzaldehydes previously processed in
batch (Table 3). Thus, compounds 7aa-7da, 7ga and 7ab were
sequentially prepared using the same flow device loaded with the
same sample of Au@APTES@SBA catalyst. Each flow experiment
-1
was allowed to run for 2 h 30 min at 200 µl min at room
temperature (residence time 18 min). To avoid crosscontamination, the column was simply rinsed with isopropanol
between two consecutive flow experiments. As a general trend,
these reductive aminations in flow took place in very high yield (up
to 99%), clearly improving the corresponding batch processes. The
less reactive p-toluidine (6b) required higher temperature (60 ºC)
and longer residence time for full conversion in the reaction with
benzaldehyde 5a. Thus, 7ab was obtained by circulating the
corresponding aldehyde and amine through the system for 5 h 45
−1
min at a combined flow rate of 100 μL min
and a reaction
temperature of 60 ºC. Also in this case, the flow process led to
higher yield (91%) than the corresponding one in batch. Overall, six
different amines were sequentially prepared in gram amounts,
achieving an accumulated TON of 434 in 18 h of operation. Under
these conditions the reductive amination led to yields as high as
99%, which clearly improve those recorded under batch conditions.
Remarkably, the employed catalyst cartridge showed no
deactivation over the whole period of use. The behavior in
isopropyl alcohol sharply contrasts with that observed in methanol.
In this last case, the presence of small silica particles in the effluent
was visible, and ICP analysis of the catalytic material showed a
substancial decrease in the amount of gold present on the catalyst
(from 3.02 % to 2.57 %) after 2.5 h use in flow for the preparation of
7aa.

Scheme 2 Other reductive amination strategies for the synthesis of
value-added products.
a)
COOH
+
CHO

b)

9a, 90% yield (R: H)
9b, 87% yield (R: Me)
9c, 90% yield (R: OMe)
9d, 80% yield (R: Br)

6a-6d

O

Au@APTES@SBA
4 (1 mol% )

NH2

OH +

O
N

Ph(Me)2SiH (3 eq)
IPA, 60 ºC, 14 h

O
10
c)

Experimental

N

Ph(Me)2SiH (2 eq)
IPA, 60 ºC, 14 h

H2N

8

R

O

Au@APTES@SBA
4 (1 mol% )

R

6a

OH

11, 75%
Au@APTES@SBA
4 (1 mol% )

NH2
O

OH
O

+
CHO

Ph(Me)2SiH (1 eq)
IPA, 60 ºC, 14 h

HN

6a

12

13, 65%

Table 3 Reductive amination of aldehydes over Au@APTES@SBA in
continuous flow.

N
H

N
H

N
H
MeO

7aa, 85% yield, TON=70

N
H
MeO
7da, 77% yield, TON=62

7ba, 89% yield, TON=72

O

N
H

7ga, 99% yield, TON=80

allowed the reductive amination of ºdifferent substrates with yields
improving those recorded under batch conditions.

7ca, 94% yield, TON=76

N
H
7ab,a 91% yield, TON=74

Combined flow rate was 100 L/min. Reactants were circulated for 5.45 h.

a

Conclusions
In summary, we have developed a new approach to reductive
amination reactions through the use of a Au@APTES@SBA
hybrid material and dimethylphenylsilane as the reducing agent.
The Au@APTES@SBA catalyst efficiently mediates the reductive
amination of a variety of aromatic and -unsaturated aldehydes
with primary (aromatic and aliphatic) and secondary amines under
mild conditions. The versatility of the as-synthesized
Au@APTES@SBA catalyst has been successfully demonstrated
in the preparation of a library of 15 secondary and tertiary
amines in isopropanol. Moreover, the new catalyst has also
allowed the synthesis of isoindolinone derivatives and the
reductive amination of biomass-derived carbonyl compounds
(furfural, 5-hydroxymethylfurfural and levulinic acid).
Finally, the suitability of Au@APTES@SBA for the multigram
production of a number of amines has been successfully
proved. The catalyst is remarkably robust and ideally suited for
scale-up and could be operated under continuous flow conditions
for ca. 18 h (TON = 434) with a stable activity-selectivity profile. In
this manner, a sequentially operated single catalyst cartridge

Materials. Tetraethyl orthosilicate (TEOS, 98%) and Pluronic (P-123)
were used as silica source and structure-directing agent,
respectively. Hydrochloric acid, tetrachloroauric acid (HAuCl4.
3H2O), Irgacure-2959, and 3-aminopropyltriethoxysilane (APTES)
were also used in the synthetic protocol to obtain the final hybrid
mesoporous material. All chemicals were purchased from Aldrich
and used as received without further purification.
Preparation of mesoporous SBA-15 silica (SBA). SBA-15 type silica
28
was prepared according to a procedure already described. 20.0 g
of pluronic (P123) were dispersed in 150 mL of water and 600 ml of
2 M HCl solution. Then, 46.6 mL of tetraethyl silicate (TEOS) were
added to the solution with stirring. This gel mixture was
o
continuously stirred at 40 C for 24 h and finally precipitated in a
o
Teflon-lined autoclave at 100 C for 48 h. Finally, the solid was
filtered, washed with deionized water, dried in air at room
o
temperature and calcined at 550 C under static air conditions for
o
-1
11 h (1.86 C min ) in order to remove the surfactant.
Preparation of amino functionalized mesoporous silica,
APTES@SBA. Modification of the mesoporous silica material with
APTES was done by stirring 5.0 g of the SBA obtained in the
previous step with 2.72 mL of APTES in toluene at room
temperature for 12 h. The white solid APTES@SBA thus obtained
was filtered, washed repeatedly with toluene and acetone, and
finally dried in air. In a final step the amino functionalized silica was
placed into a soxhlet system and was washed with acetone for 15
hours to remove the un-reacted APTES.
Preparation of Gold nanoparticles functionalized mesoporous
silica, Au@APTES@SBA. Synthesis and incorporation of AuNPs into
the silica network was carried out by using a one-pot strategy based
29
on that proposed by McGilvray and co-workers. 0.30 g of
HAuCl4.3H2O were added to an aqueous mixture (230 mL) of the
APTES@SBA solid (5.0 g). Then, 0.51 g of Irgacure-2959 were added
and the yellow solution was placed into a photoreactor and
irradiated with 16 UVA lamps for 30 min. The final pink solution was
then filtered and washed several times with water to remove the
non-reacted salt. The air-dried new synthesized hybrid materials
were denoted as Au@APTES@SBA (3 wt % Au attending to ICP
analyses). The procedure led to 100 % of incorporation of the gold
used during the synthesis of the hybrid material.
General procedure for catalytic reductive amination in batch.
Aldehyde (0.50 mmol), amine (0.50 mmol), dimethylphenylsilane
(0.75 mmol), isopropanol (1 mL) and the Au@APTES@SBA catalyst
(Au: 1.0 mol%) were placed into a 10 mL vial under a N2
atmosphere. The resulting mixture was vigorously stirred at the
corresponding temperature for a given reaction time (see Scheme
2). After completion of the reaction, the supported catalyst was
separated by filtration and the reaction mixture was concentrated
under vacuum and then purified by flash chromatography
(cyclohexane:ethyl acetate) to afford the corresponding product.
General procedure for catalytic reductive amination in flow.
The reactor was set up by introducing the Au@APTES@SBA (ca.
0.50 g) in a glass Omnifit® column (10 mm bore size and up to
maximal 70 mm of adjustable bed height). The column was fed with
two independent streams, each connected to a syringe pump.
Solution A contained a mixture of the selected aldehyde and amine
and solution B was prepared with the corresponding amount of
phenyldimethyl-silane as reducing agent. Reactions were
performed at rt or 60 º C depending on the optimized conditions

revealed in batch. In all cases, the collected organic phase was
concentrated and the obtained residue was purified by flash
column chromatography.

Conflicts of Interest
There are no conflicts of interest to declare.

Acknowledgements
This work was funded by the CERCA Programme/Generalitat de
Catalunya, and MINECO (grant CTQ2015-69136-R and Severo Ochoa
excellence accreditation award 2014-2018 (SEV-2013-0319)). A. I.
Carrillo acknowledges the COFUND-Marie Curie action of the
European Union’s FP7 (291787-ICIQ-IPMP) for a postdoctoral
fellowship.

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