Efficient One-Pot Reductive Aminations of Carbonyl Compounds with Aquivion-Fe as a Recyclable Catalyst and Sodium Borohydride

Article abstract of DOI:10.1002/ejoc.201901614

A one-pot reductive amination of aldehydes and ketones with NaBH₄ was developed with a view to providing efficient, economical and greener synthetic conditions. A recyclable iron-based Lewis catalyst, Aquivion-Fe, was used to promote imine formation in cyclopentyl methyl ether, followed by the addition of a small amount of methanol to the reaction mixture to enable C=N reduction by NaBH₄. The protocol, applied to a wide number of amines and carbonyl compounds, resulted in ever complete conversion of these latter with excellent chemoselectivity towards the expected amination products in the most cases. Isolated yields, determined for a selection of the screened substrates, were found consistent with the previously obtained conversion and selectivity data. Cinacalcet, an important active pharmaceutical ingredient, was efficiently prepared by the title procedure.

Full text of DOI:10.1002/ejoc.201901614

A Journal of
Accepted Article
Title: Efficient one-pot reductive aminations of carbonyl compounds
with Aquivion-Fe as a recyclable catalyst and sodium borohydride
Authors: Veronica Airoldi, Oreste Piccolo, Gabriella Roda, Rebecca
Appiani, Francesco Bavo, Riccardo Tassini, Stefano
Paganelli, Sebastiano Arnoldi, Marco Pallavicini, and
Cristiano Bolchi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901614
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901614
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10.1002/ejoc.201901614
European Journal of Organic Chemistry
FULL PAPER
Efficient one-pot reductive aminations of carbonyl compounds
with Aquivion-Fe as a recyclable catalyst and sodium borohydride
Veronica Airoldi,[a] Oreste Piccolo,[b] Gabriella Roda,[a] Rebecca Appiani,[a] Francesco Bavo,[a] Riccardo
Tassini,[c] Stefano Paganelli,[c] Sebastiano Arnoldi,[a] Marco Pallavicini,[a] and Cristiano Bolchi *[a]
Abstract: A one-pot reductive amination of aldehydes and ketones
with NaBH4 was developed with a view to providing efficient,
economical and greener synthetic conditions. A recyclable iron-based
Lewis catalyst, Aquivion-Fe, was used to promote imine formation in
cyclopentyl methyl ether, followed by the addition of a small amount
are generally classified depending on how the reduction of
the intermediate imine or iminium ion is done. 3 Two are the
main options: hydrogenation with hydrogen or hydrogen
donors and reduction by the use of compounds or complex
systems (hydride reagents) acting as a hydride source
of methanol to the reaction mixture to enable C=N reduction by NaBH4. (Figure 1). Both the approaches have been widely explored
The protocol, applied to a wide number of amines and carbonyl
compounds, resulted in ever complete conversion of these latter with
excellent chemoselectivity towards the expected amination products
in the most cases. Isolated yields, determined for a selection of the
screened substrates, were found consistent with the previously
obtained conversion and selectivity data. Cinacalcet, an important
active pharmaceutical ingredient, was efficiently prepared by the title
procedure.
and developed in the past decades by using a large variety
of reducing agents and catalysts.
R3
R1
R4
R2
R4
R3
R3
R4
R3
R1
R4
+
N+
N
N
N
H
H
(cat)
N
H
hydride
source
R1
R3
R2
R2
+
OH
O
-H O
2
4
hydride
proton source
R1
R2
R
= H
R1
R2
Introduction
Figure 1. Proposed mechanism of reductive amination with a hydride
source.
Many different strategies have been developed for the synthesis
of amines. The vast majority of them can be summarized and
classified as: (i) alkylation of ammonia and amines; (ii) reduction
of nitrogen containing groups; (iii) Gabriel synthesis and (iv)
reductive amination (RA) of carbonyl compounds. The latter is the
most widely used method and novel protocols, reactants and
catalysts are currently sought to improve it.1-10 Its success has
been determined by commercial availability of the substrates, mild
reaction conditions, sustainable and economical protocol, high
atom economy without toxic wastes, high tolerance to other
functional groups, chemoselective conversion to secondary or
tertiary amine. By this method, for instance, amine nitrogen
deprotection and subsequent alkylation can be safely relegated to
the ultimate step in the synthesis of polyfunctionalized amines.11-
13 Its attractiveness has been further increased by practicability in
a single one-pot operation (direct reductive amination, DRA) by
mixing carbonyl compound, amine and a suitable reducing agent
without isolation of imine intermediates.2,14-16
However, it was only after 2000 that search for new RA
methods began to conjugate efficiency and economic
viability with environmental benignity, in particular of the
reducing agent. Indeed, recently drafted green criteria for RA
are mainly focused on the choice and the amount of the
reductants: H2/metal catalyst is preferred over the others
and, in case of hydride reagents, sodium borohydride (SB) is
18
the best option. However, though recommended, the use
of hydrogen is not compatible with other reducible functional
groups and requires expensive and toxic metals as catalysts.
On the other hand, SB is safe, quite inexpensive and water
tolerant. Ease of work-up and good atom economy (81%) 19
characterize its use. However, SB is usually unsuitable for
DRA due to the competitive reduction of starting carbonyls.
Its addition has to be postponed after imine formation, which
is often far from reaching completeness. Alternative borane-
based reducing agents, such as sodium cyanoborohydride
(SCB), sodium triacetoxyborohydride (STAB) and picoline-
borane complex (Pic-B), selectively reduce the in situ
generated imine driving conversion of carbonyl compound
into imine to completeness and enabling one-pot
procedures.20 But they are not advantageous in terms of
atom economy and, for a number of reasons, they do not
satisfy safety and/or cost criteria. Last but not least, RA
should be accomplished in more environmentally friendly
solvents in replacement of less desirable solvents such as
dichloromethane (DCM), THF and DMF.20
Since the first report almost a hundred years ago,17 RA has
been declined in a multitude of different procedures, which
[a]
Dipartimento di Scienze Farmaceutiche
Università degli Studi di Milano
via Mangiagalli 25, Milano, I-20133 Italy
E-mail: cristiano.bolchi@unimi.it
https://sites.unimi.it/pallab/
[b]
[c]
SCSOP
via Bornò 5, Sirtori (LC), I-23896 Italy
Dipartimento di Scienze Molecolari e Nanosistemi
Università Ca’ Foscari Venezia
Via Torino 155, Venezia Mestre, I-30170 Italy
As is evident from the above, a number of issues has to be
simultaneously addressed in designing a sustainable and
efficient DRA: greener solvent, environmentally acceptable
and safe reductant, such as SB, and one-pot protocol. In
Supporting information for this article is available on the WWW
under
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10.1002/ejoc.201901614
European Journal of Organic Chemistry
FULL PAPER
order to meet the above requirements, a DRA method cannot
work without a suitable catalysis promoting efficient imine
formation before SB exerts its unselective reduction power.
Here we report our efforts in developing a DRA procedure
with such features. A number of aldehydes and ketones were
reductively aminated with different amines using SB in
cyclopentyl methyl ether (CPME), preferably chosen among
other advisable solvents, and in the presence of a recyclable
Lewis acid, the iron salt of Aquivion-H (Aquivion-Fe) (Figure
2),21 catalysing the imine formation. We report also the
recycling of this catalyst and the extension of the method
from model substrates to Cinacalcet, an important active
pharmaceutical ingredient.22
benzylaniline with a minority presence of benzyl alcohol and
aniline. As expected, benzaldehyde and the intermediate
imine were absent. These analytical data indicated that the
conversion degree (CV%) of benzaldehyde was 100%. The
selectivity towards the desired N-benzylaniline was 71% as
indicated by the integration of the singlet due to its CH2
compared to that of the CH2 of the other product, the
undesired benzyl alcohol. The minority, but not negligible
formation of benzyl alcohol could be reasonably imputed to
incomplete imine formation in the DRA first step.
Undoubtedly, the imine formation was minimal without
catalyst. In its absence, we observed complete conversion of
benzaldehyde into benzyl alcohol and N-benzylaniline but
with a very low amination selectivity (5%), thus proving the
essential role played by Aquivion-Fe.
Searching for more eco-friendly solvents
After ascertaining that Aquivion-Fe efficiently catalyzed the
conversion
of
benzaldehyde
and
aniline
into
benzylideneaniline in DCM and that the successive addition
of methanol enabled its reduction to benzylaniline, we moved
on to replacement of DCM with solvents having acceptable
EHS (Environmental, Health, Safety) properties. In 2013,
dimethyl carbonate and ethyl acetate were proposed as
successful green alternatives to chlorinated solvents, THF
Fig. 2. Chemical structure of Aquivion-H and Aquivion-Fe
and DMF after
a selection based on 360 reductive
aminations accomplished between two aldehydes and six
amines in ten different solvents using SCB, STAB or pic-B as
reducing agents. 20 On our part, we needed a solvent stable
under basic conditions, compatible with hydrides and, above
all, apolar enough to avoid SB solubilisation and to exclude
its reducing action during the DRA first stage. The choice,
inspired by the recently reported replacement of banned
Results and Discussion
DRA with Aquivion-Fe and SB in DCM
It is known that SB alone may not afford excellent DRA
yields. Poor nucleophilic amines, poor electrophilic carbonyls
and sterically encumbered reactive centers result in
incomplete imine formation. The use of Brønsted and Lewis
acids facilitate imine formation and, according to some
authors, also imine reduction coordinating carbonyl oxygen
and imine nitrogen respectively. 16,23-29 In particular, special
attention has been paid to catalysts based on iron, a non-
toxic, environmentally acceptable and inexpensive metal.27,28
Recently, the efficient activity and recyclability as a Lewis
catalyst in Friedel-Crafts acylations of the iron salt of
Aquivion-H (fig. 2) has been reported.21 Aquivion-H is a
commercially available perfluorosulfonic ionomer, used to
prepare polymer electrolyte membranes.30
We started considering the conversion of benzaldehyde into
N-benzylaniline by treatment with equimolar aniline and SB
as a model reductive amination. First, the reaction was
carried out in DCM and in the presence of 3.3 mol%
Aquivion-Fe. After 3 hours at 40 °C, a methanol amount
equal to one fifth of DCM was added dropwise at 0 °C. After
30 minutes, the reaction mixture was washed with water and
the catalyst was recovered by filtration. The aqueous phase
was separated and extracted with DCM. The two organic
layers were combined and concentrated. The resultant
residue, analysed by 1H NMR, was the desired N-
solvents in L
-amino acids esterification,31-33 fell on the green
ethers tert-amyl methyl ether (TAME), cyclopentyl methyl
ether (CPME) and 2-methyl-tetrahydrofuran (Me-THF) and
on p-cymene, which is much less toxic than toluene. By the
same protocol previously used in DCM, benzaldehyde was
completely converted into benzylaniline and benzyl alcohol
with a selectivity of 94% in TAME, of 91% in CPME, of 57%
in Me-THF and of 97% in p-cymene. Difficult removal of high
boiling p-cymene, high cost of TAME and the lower efficiency
of Me-THF prompted us to select CPME as a preferable
solvent. In the absence of catalyst, we noted that the
benzylaniline formation was modest (17% selectivity) in
CPME but not so negligible as in DCM (5% selectivity). This
would indicate that the solvent plays some role in imine
formation and that the considerable amount of benzyl alcohol
resulting from the DRA in DCM in the presence of the catalyst
might be imputed, as previously hypothesized, to a less
efficient imine formation rather than to an anticipated SB
reducing action. In fact, in DCM, which has solvent
characteristics very similar to those of CPME, SB should be
as unable to exert its reducing action as in CPME. Different
is the case of the other ether, Me-THF, which is significantly
more polar than CPME and DCM. In this solvent, where
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10.1002/ejoc.201901614
European Journal of Organic Chemistry
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benzyl alcohol and N-benzylaniline were formed in
comparable amounts in the presence of the catalyst, it is
reasonable that SB partially acts reducing unreacted
benzaldehyde before methanol addition. DRA of
benzaldehyde with aniline without catalyst was
accomplished also in Me-THF. As expected, the already
modest 57% selectivity towards N-benzylaniline registered in
the presence of Lewis catalysis resulted in a negligible 7% in
its absence.
Lastly, we considered the use conditions of methanol in the
DRA of benzaldehyde with aniline in CPME. Addition of
methanol at room temperature without cooling caused
temperature enhancement and, concomitantly, incomplete
imine reduction was observed. Use of methanol amounts
lower than one fifth of the CPME volume led to incomplete
imine reduction as well as to less favourable final
benzylaniline/benzyl alcohol ratio.
reaction mixture could contribute to the catalysis. Indeed,
such an eventuality should be excluded because we did not
observe any reductive amination of benzaldehyde with
aniline when we applied our DRA protocol without Aquivion-
Fe using CPME previously stirred in the presence of
Aquivion-Fe and SB at 40 °C for 3 hours and then filtered
before SB reintegration and addition of the two substrates.
Titration with 0.1 M NaOH of Aquivion-H confirmed the
declared 870 equivalent weight of the unsalified ionomer,
while, as expected, we registered no titrant consumption by
fresh Aquivion-Fe and recycled Aquivion-Fe as proof of its
complete and permanent salification resulting from treatment
with iron powder.
An issue to be addressed was the advantage from using
Aquivion-Fe instead of its immediately available precursor
Aquivion-H. This, in the same way as other carbon-based
solid Brønsted acids,24 should be able to favour imine
formation. Indeed, when used in catalytic amount (3.3
mol%), Aquivion-H showed lower efficiency than that of
Aquivion-Fe. Moreover, as expected, it was recovered
devoid of any acidic character and therefore not directly
recyclable, unlike Aquivion-Fe, in successive DRAs.
As outlined above, the presence of Aquivion-Fe was
essential in the one-pot RA of benzaldehyde with aniline and
SB. In its absence, we had almost quantitative conversion
into benzyl alcohol and minimal amount of benzylaniline.
Furthermore, we wished to assess whether it was
determinant in both the formation and the reduction of imine.
Therefore, we repeated the reaction in CPME removing SB
and Aquivion-Fe after 3 hours reaction at 40 °C, re-adding
SB to the filtrate at room temperature and adding, after
cooling to 0 °C, methanol. Under such conditions where the
catalysts was excluded from the reduction step, the yield of
benzylaniline was analogous to that obtained without
Aquivion-Fe removal. This indicates that the main role of the
catalytic system is to favour the formation of the intermediate
imine.
The catalyst: characterization, role and recycling
Before extending the new amination protocol to other
carbonyl compounds and amines, we verified the
recyclability of our iron based catalyst and its ability to
maintain the initial metal content through repeated catalytic
cycles. We chose the conversion of benzaldehyde (0.5 g)
into dibenzylamine by treatment with equimolar benzylamine
as a model reaction. The imine was formed in CPME at 40
°C in the presence of 3.3 mol% Aquivion-Fe and of
undissolved stoichiometric SB. After 3 hours, methanol was
added at 0 °C to enable reduction by SB. The reaction was
prolonged to 30 minutes and then worked up as previously
described for the reaction in DCM, but using EtOAC to
extract the aqueous phase. Benzaldehyde was converted
into dibenzylamine with 91% selectivity. The catalyst,
recovered by filtration, was washed with acetonitrile, dried
and reused nine times for the same reaction and under the
same conditions. In the further nine reductive aminations,
benzaldehyde was completely converted into amine and
benzyl alcohol with selectivity towards amine ranging from
91% to 98%.
Screening of carbonyl compounds and amines
As recently outlined, “consistently high yields in repeated
runs cannot be taken as satisfactory evidence for high
catalyst stability” although “they testify to the robust nature of
a catalyst system, which is a necessary requirement for long-
term uses”.34 Therefore, while not seeing catalyst
performance drops through the ten cycles, we monitored the
iron content of the catalyst as a stability index. We used
Aquivion-H (R-SO3H) powder having a nominal equivalent
weight of 870 g/eq to prepare Aquivion-Fe ((R-SO3)3Fe),
whose theoretical iron loading was therefore 2.10% (w/w%).
The initial metal content, measured by ICP-OES, was 2.35%;
after ten cycles, the metal loading was 1.92%. The found
values indicate that the Aquivion-H salification procedure
was effective in quantitatively exchanging the sulfonic acid
functions and that extended recycling resulted in a limited
drop of the initial metal loading. This observation raised the
question whether minimal iron loss from the catalyst into the
After designing the two-step/one-pot reductive amination in
DCM/methanol, replacing DCM with CPME and
demonstrating Aquivion-Fe catalyst recyclability, the fourth
step of our investigation was the extension of the method to
other carbonyl compounds and amines applying the protocol
followed for the reaction benzaldehyde-benzyl amine. Forty-
one reactions were planned. The selectivity towards the
desired amine was determined by 1H NMR analysis of the
crude resulting from the reactions work-up, by comparing the
integrations of two diagnostic peaks, one unequivocally
ascribable to amine product and the other to the undesired
alcohol side-product. Furthermore, the same crude products
were GC/MS analysed to ascertain the identity of the amine
produced by the reductive amination.
First, benzaldehyde was reacted with fifteen amines (Table
1). These were: seven primary aromatic amines (aniline, p-
chloro-, m-chloro-, p-bromo-, p-methoxy-, p-methyl- and p-
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10.1002/ejoc.201901614
European Journal of Organic Chemistry
FULL PAPER
trifluoromethyl-aniline; entries 1-7), three primary arylalkyl
Application of the procedure to some selected
substrates and to Cinacalcet
amines (benzylamine,
-methylbenzylamine and 2-
phenylethylamine; entries 8-10), two primary alkyl amines (t-
butylamine and cyclohexylamine; entries 11 and 12) and
three secondary alicyclic amines (piperidine, pyrrolidine and
morpholine; entries 14-16). Benzaldehyde was aminated
also with aqueous ammonia (entry 13). In this case, SB and
methanol addition was postponed to imine formation.
Benzaldehyde was always completely converted with
selectivity towards the sixteen different benzylamines
generally ranging from good to excellent. Relatively lower or
moderate selectivities were encountered only when aniline
bears an electron withdrawing substituent (chloro, bromo,
trifluoromethyl; Table 1, entries 2-4 and 7) and with hindered
primary alkylamine (t-butylamine; Table 1, entry 11). In the
case of the three secondary alicyclic amines, which
contribute to SB solubilisation, CPME had to be replaced with
less polar p-cymene, to procrastinate SB reductant action to
methanol addition, and the reaction temperature was
lowered to 20 °C to promote iminium formation. So, the
selectivities were very high (Table 1, entries 14-16).
The above protocol of one-pot reductive amination was
applied to a representative selection of the previously
screened carbonyl compounds and amines this time isolating
the amination products 1a-1r (Table 5) by chromatography
in order to verify the consistency, expected on the basis of
the 100% conversions, between yields and previously
observed selectivities. The isolated yields of the selected
eighteen aminations, reported in Table 5, confirm such an
expectation. In fact, compared with the corresponding
amination selectivities listed in the tables 1-4, they are all
only a few percent points lower as expectable after a
chromatographic separation.
At the end of the investigation, to showcase the synthetic
utility of the developed DRA, we wished to apply this
amination procedure to the preparation of an active
pharmaceutical ingredient. We chose the calcimimetic
Cinacalcet, a secondary amine obtainable by different
synthetic approaches, 35 among which reductive amination of
In the second set of aminations (Table 2), aniline was reacted
with twelve aldehydes: seven substituted benzaldehydes (p-
methyl, p-chloro, p-cyano, p-nitro, p-methoxy, o-methoxy-
3-(3-trifluoromethylphenyl)propionaldehyde with (R)-1-(-
naphthyl)ethylamine ((R)-1-NEA) is one of the most
36
industrially applied methods (Fig. 3). Based on our long-
and
o-chloro-benzaldehyde;
entries
1-7),
2-
acquired familiarity with chlorinated isocyanurates,37-41 mild,
green oxidants and halogenating agents,42,43 we decided to
prepare the aldehyde by oxidation of the corresponding
alcohol with trichloroisocyanuric acid (TCCA) instead of
applying procedures previously reported in papers and
patents.44-48 The conversion was quantitative and the crude
aldehyde, isolated by simple extraction, could be directly
aminated without chromatographic purification or conversion
into Bertagnini adduct. The reaction with (R)-1-NEA was
carried out as described above for benzaldehyde with
benzylamine. Cinacalcet was isolated in 76% yield as
hydrochloride by crystallization (Table 5, entry 19).
Compared to the reported reductive aminations of 3-(3-
trifluoromethylphenyl)propionaldehyde with (R)-1-NEA, this
procedure shows analogous efficiency offering the
advantage of using SB and crude aldehyde in a green
solvent according to a simple one-pot protocol.
furancarbaldehyde, cinnamaldehyde, picolinaldeheyde,
isonicotinaldehyde, and cyclohexanecarbaldehyde (entries
8-12). Again, the conversion of the aldehydes was complete
and the selectivities towards N-alkylated aniline were all from
good to very high. Here, the substitution pattern of
aldehydes, possibly because of the role played by the Lewis
catalyst, turned out to be less determinant than that of aniline
in the previous set of benzaldehyde aminations.
In the third set of aminations, seven in all, benzylamine or
cyclohexylamine were reacted with aromatic aldehydes other
than benzaldehyde (Table 3). The reactions of the aldehydes
were complete and the selectivity towards the desired
products were from high to very high.
Lastly, we considered ketones (Table 4), whose carbonyl
carbon is notoriously less susceptible of electrophilic attack
than that of aldehydes for both steric and electronic factors.
Indeed, cyclohexanone was reductively aminated by p-
methoxyaniline with a moderate 44% selectivity under the
same conditions adopted for aldehydes (entry 2), while
amination of cyclohexanone and its 4-methyl derivative with
unsubstituted aniline required a higher temperature (80 °C)
to reach analogous selectivity degrees (entries 1 and 3).
Aromatic ketones (acetophenone and its p- methyl and p-
chloro derivatives) were even less prone to amination. Their
reaction with aniline had to be prolonged to 6 hours to get
modest or moderate amination selectivity (entries 4-6).
CF3
H
N
H2N
Aq-Fe,NaBH , CPME, 3 h,
4
CF3
40 °C; MeOH, 30 min, rT.
+
O
(R)-1-NEA
Figure 3. Preparation of Cinacalcet by reductive amination of 3-(3-
trifluoromethylphenyl)propionaldehyde with (R)-1-(
((R)-1-NEA).
-naphthyl)ethylamine
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10.1002/ejoc.201901614
European Journal of Organic Chemistry
FULL PAPER
Conclusions
Table 1. Reductive aminations of benzaldehyde (Aq-Fe, NaBH4, CPME, 40 °C,
3h and then MeOH, rT, 30 min).
In summary, we have developed an efficient and sustainable
reductive amination protocol that meets some very desirable
requirements: the use of a recoverable and recyclable
catalyst, based on a non-toxic metal, in greener solvents with
an inexpensive and eco-friendly reductant realising a one-pot
procedure. Aquivion-Fe has been proved to catalyse the
amination of a number of aldehydes and ketones with
primary and secondary amines and to be reusable several
times. The use of the green ether CPME (and, where
necessary, of cymene) and the delayed addition of methanol
have allowed sodium borohydride, a largely available, but
unselective reductant, to be used in a one-pot procedure with
high chemoselectivity for reductive amination versus C=O
reduction. The model reaction has been successfully applied
to the preparation of nineteen amines, among which the
active pharmaceutical ingredient Cinacalcet.
R2
N
OH
R1
CHO
R1-NH
R1-NH
R2
+
+
+
R2
2
1
unreacted
R1
Ph
R2 Conv. %[a]
1
Sel. %[b]
91
2
Sel. %[c]
Run
1
2
H
H
100
100
9
58
42
Cl
Cl
3
H
100
51
49
4
5
6
H
H
H
100
100
100
54
84
81
46
16
19
Br
MeO
Me
7
8
9
H
H
H
100
100
100
47
92
90
53
8
F3C
Bn
10
10
11
H
H
100
100
90
31
10
69
12
13
Cy
H
H
H
100
100
70
98
30
2
14
15
100[d]
91
81
9
100[d]
19
16
O
100[d]
95
5
[a] Percent conversion of benzaldehyde. [b] Selectivity towards 1. [c] Selectivity
towards 2. [d] p-cymene, 20 °C, 3 h.
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10.1002/ejoc.201901614
European Journal of Organic Chemistry
FULL PAPER
Table 2. Reductive aminations of aldehydes with aniline (Aq-Fe,
Table 3. Reductive aminations of aldehydes with benzylamine or
cyclohexylamine (Aq-Fe, NaBH4, CPME, 40 °C, 3h and then MeOH, rT,
30 min).
NaBH4, CPME, 40 °C, 3h and then MeOH, rT, 30 min).
NH2
HN
R1
NH2
OH
R1
OH
R1
+
+
+
CHO
R2 NH2
R1 CHO
+
R1
NH2
R2
+
+
HN
R2
R1
1
2
unreacted
2
1
unreacted
R1
R2
Bn
Conv. %[a]
100
1
Sel. %[b]
77
2
Sel. %[c]
23
Run
R1
Conv. %[a]
100
1
Sel. %[b]
81
2
Sel. %[c]
19
Run
1
1
2
3
Me
Cl
Me
Cl
Bn
Bn
100
100
100
100
83
0
17
0
2
3
4
5
100
100
100
100
79
67
66
72
21
33
34
28
MeO
NC
4
5
Bn
Cy
100
O
O N
2
100
100
82
67
18
33
O
MeO
OMe
6
7
Cy
Cy
OMe
6
7
100
100
88
64
12
36
100
86
14
Cl
[a] Percent conversion of aldehyde. [b] Selectivity towards 1. [c] Selectivity
towards 2.
8
9
100
100
66
72
34
28
O
N
10
100
100
100
81
70
80
19
30
20
11
12
N
[a] Percent conversion of aldehyde. [b] Selectivity towards 1. [c] Selectivity
towards 2.
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10.1002/ejoc.201901614
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Table 4. Reductive aminations of ketones with aniline (Aq-Fe, NaBH4, CPME,
Table 5. Isolated yields of reductive aminations (Aq-Fe, NaBH4, CPME, 40 °C,
40 °C or 80 °C, 3 or 6 h and then MeOH, rT, 30 min).
3h and then MeOH, rT, 30 min).
R2
Yield
%
Run Carbonyl compound Amine
Product
NH2
NH2
HN
R1
1
Benzaldehyde
Aniline
1a 86
R1
OH
R1
O
N
H
+
+
+
R2
R2
Cl
2
3
Benzaldehyde
Benzaldehyde
p-Cl-aniline
1b 55
1c 90
N
H
R3
R3
R3
2
1
unreacted
N
H
BnNH2
4
Benzaldehyde
2-PEA
1d 85
N
H
R1
R2
R3 Conv. %[a]
1
Sel. %[b]
50
2
Sel. %[c]
50
Run
5
6
7
Benzaldehyde
Benzaldehyde
p-Tolualdehyde
CHA
Piperidine
Aniline
1e 68
1f 84[a]
1g 77
N
H
1
2
3
4
H
OMe
H
100[d]
100[e]
100[d]
100[f]
N
44
48
45
56
52
55
N
H
Me
NC
O2N
MeO
8
9
p-CN-Benzaldehyde
p-NO2-Benzaldehyde
4-Anisaldehyde
Aniline
Aniline
Aniline
Aniline
1h 63
1i 60
N
H
Me
H
N
H
Me
Cl
100[f]
100[f]
35
18
65
82
10
11
1j
70
N
H
5
6
Me
Me
H
H
NH
o-Anisaldehyde
1k 82
1l 69
OMe
12
Cinnamaldehyde
Aniline
N
H
[a] Percent conversion of ketone. [b] Selectivity towards 1. [c] Selectivity
towards 2. [d] 3 hours at 80 °C. [e] 3 hours at 40 °C. [f] 6 hours at 80 °C.
13 Formylcyclohexane
Aniline
BnNH2
BnNH2
1m 73
1n 96
1o 81
N
H
N
H
14 p-Cl-benzaldehyde
Cl
N
H
15
16
4-Anisaldehyde
MeO
OMe
HN
o-Anisaldehyde
CHA
1p 61
17
18
Cinnamaldehyde
Cyclohexanone
CHA
1q 84
N
H
Aniline
1r 47[b]
N
H
F3C
19
(R)-1-NEA
Cinacalcet
76
CHO
[a] p-Cymene, 20 °C, 3 h. [b] 3 h at 80 °C.
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[30] Solvay Speciality Polymers SpA.
Acknowledgements
https://www.sintef.no/globalassets/upload/materialer_kjemi/energikonve
rtering-og-materialer/bilder/merlo-fuel-cell-science-technology-berlin-
11-12-april-2012.pdf
We are grateful to Dr. Claudio Oldani and Solvay Specialty
Polymers Italy S.p.A. for the sample of Aquivion-H and for
the metal analysis of metallized resin.
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Keywords: Amination • Aquivion • Chemoselectivity • Cinacalcet
• Sodium borohydride
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10.1002/ejoc.201901614
European Journal of Organic Chemistry
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FULL PAPER
Aldehydes and ketones were reductively
aminated by a one-pot procedure using
a recyclable iron-based Lewis catalyst,
One-pot reductive amination
Aquivion-Fe catalysis
Aquivion-Fe,
to
promote
imine
Veronica Airoldi, Oreste Piccolo,
formation, and NaBH4 as a reductant in
cyclopentyl methyl ether and methanol.
Gabriella Roda, Rebecca Appiani,
Francesco Bavo, Riccardo Tassini,
Stefano Paganelli, Sebastiano Arnoldi,
Marco Pallavicini, and Cristiano Bolchi*
The
developed
protocol
was
successfully applied to the preparation
of Cinacalcet, an important active
pharmaceutical ingredient.
Page No. – Page No.
Efficient one-pot reductive
aminations of carbonyl compounds
with Aquivion-Fe as a recyclable
catalyst and sodium borohydride
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