Ammonium formate as a green hydrogen source for clean semi-continuous enzymatic dynamic kinetic resolution of (+/-)-α-methylbenzylamine

Article abstract of DOI:10.1039/c4ra00462k

The chemoenzymatic dynamic kinetic resolution of (+/-)-α- methylbenzylamine under continuous flow conditions in the presence of Pd/BaSO₄ as racemization catalyst and ammonium formate as reductant is described. Under the conditions good conversions and excellent enantiomeric excess are reported. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00462k

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Ammonium formate as a green hydrogen source for
clean semi-continuous enzymatic dynamic kinetic
resolution of (+/ꢀ)-a-methylbenzylamine
Cite this: RSC Adv., 2014, 4, 13620
*
Amanda S. de Miranda, Rodrigo O. M. A. de Souza and Leandro S. M. Miranda
Received 16th January 2014
Accepted 26th February 2014
The chemoenzymatic dynamic kinetic resolution of (+/ꢀ)-a-methylbenzylamine under continuous flow
conditions in the presence of Pd/BaSO4 as racemization catalyst and ammonium formate as reductant is
described. Under the conditions good conversions and excellent enantiomeric excess are reported.
DOI: 10.1039/c4ra00462k
www.rsc.org/advances
in the high nucleophilicity of primary amines. This inherent
nucleophilicity leads to a competition between enzymatic and
Introduction
chemical acylation in the kinetic resolution step, as well as
trapping of the imine intermediate and its deamination, which
is responsible for the low selectivity for the desired racemic
amine in the racemization process.
Recently, continuous processing and biocatalysis have been
elected as key green emerging research areas for sustainable
manufacturing1a and it is clear that joint efforts between these
areas can lead to great improvements in continuous
manufacturing in agreement with green chemistry
principles.1b,c
Optically pure amines are ubiquitously present in nature and
active pharmaceutical ingredients (APIs). However, their
synthesis still represents an ongoing synthetic challenge that
can be inferred by the great amount of work and methodologies
dealing with this issue in the literature.
Over the years, several methods have been developed,
including the multi-step protocol addition of carbanions to
chiral sulphinyl, sulphonyl or phosphoryl imines;2 the hydro-
genation of acyl enamines with chiral phosphorus ligands;3
transition metal and organocatalyzed asymmetric imine
reduction,4 asymmetric hydroamination of olens5 and kinetic
resolutions. All of these methodologies suffer from limited
scope, greenness and no denitive approach exists.
Among them, enzymatic kinetic resolution has proven to be
useful for the preparation of enantioenriched primary chiral
amines due to its low operational and catalyst cost being
generally more suitable concerning green chemistry principles.
In this process, a racemate is resolved through enantioselective
enzymatic acylation, providing enantioenriched amide and an
amine with the opposite conguration.6 If only one enantiomer
is desired, a metal catalyzed racemization reaction can be
coupled with the kinetic resolution in a one-pot procedure, a
process known as dynamic kinetic resolution (DKR).7
Reetz and co-workers8 reported the rst example of chemo-
enzymatic DKR of amines, by using palladium on carbon to
promote racemization of the amine and Novozyme 435
(commercial immobilized Candida antarctica lipase B – CALB)
to achieve enantioselective acylation. However, moderate
conversion was observed only aer 8 days. Since then, many
other approaches towards the biocatalyzed DKR of amines have
been developed,6a,b most of them based on free CALB or its
immobilized form as biocatalyst for the kinetic resolution step.
On the other hand, racemization is still a challenge and several
methods have been developed based on Pd, Ni, Ru and Ir
catalysts.7c
In the case of palladium, catalysts supported on heteroge-
neous basic supports have proven to be very useful for DKR of
amines.9 However, Pd promoted racemizations are usually
accomplished under harsh conditions, such as high tempera-
tures, in which lipase activity can be compromised. Besides,
amine racemization is prone to formation of by-products
derived from reaction of imine with unreacted amine. In Fig. 1
is depicted the catalytic cycle that leads to the racemization
process as well as the collateral reactions that lead to the
observed by-products. In order to circumvent such drawbacks
the use of a reductive atmosphere, such as the presence of
hydrogen gas, is usually required.9a,b
In such context, the use of continuous ow technology can
offer some solutions to the above mentioned scenario, as it
allows one to conduct the racemization and lipase-catalyzed
kinetic resolution in different compartments leading to the
maximization of both transformations, independently.
However, this approach has not been fully exploited since only
few examples of DKR of amines under continuous ow condi-
tions have been reported.10
The dynamic kinetic resolution of amines is a developing
eld. When compared to the DKR of chiral secondary alcohols
the resolution of amines presents additional challenges rooted
Federal University of Rio de Janeiro, Biocatalysis and Organic Synthesis Lab,
Chemistry Institute, Av athos da Silveira Ramos, Rio de Janeiro, Brazil. E-mail:
leandrosoter@iq.ufrj.br
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Fig. 1 The racemization cycle and the by-products observed in the dynamic kinetic resolution of 1.
In the present work we describe the use of ammonium
With this information in hands we decided to begin with
formate as an alternative and greener hydrogen source for Pd- commercially available Pd nanoparticles entrapped in AlO(OH)
promoted racemization and DKR of (+/ꢀ)-a-methylbenzyl- matrix (Table 1).
amine. To the best of our knowledge, use of ammonium
As depicted in Table 1, commercial Pd nanocatalyst entrap-
formate in chemoenzymatic dynamic kinetic resolutions has ped in aluminum hydroxide matrix was not able to racemize
not been reported yet. Additionally, we report our efforts (S)-(ꢀ)-a-methylbenzylamine with acceptable selectivity when
towards the development of a continuous ow dynamic kinetic no source of hydrogen was used. However, complete racemi-
resolution of (+/ꢀ)-a-methylbenzylamine.
zation was achieved aer 3 h with catalyst loading of 5 mol%
(entry 3, Table 1). Under these conditions large amounts of by-
products were observed, mainly secondary amine and aceto-
phenone. It is worth mentioning that successful racemization of
amines reported by Kim and co-workers11 was achieved with
non-commercial Pd nanocatalyst entrapped in aluminum
hydroxide matrix, whose efficiency is affected by the methods of
preparation and is related to the size and surface area of
nanoparticles.
As pointed out by others, the observed by-products may be due
to the building up of concentration of the imine intermediate in
the reaction media, which is trapped by the unreacted amine.9a,b,11a
Molecular hydrogen has been used in Pd promoted racemizations
in order to improve efficiency and selectivity.9a,b,11a In fact, some
racemization of chiral secondary alcohols and most Pd promoted
racemization and DKR of amines are carried out under reductive
Results and discussion
As reported in the previous paragraphs, racemization repre-
sents the most challenging step in the context of DKR of
amines. Before moving towards a continuous ow procedure we
decided to begin studying the racemization process by
screening catalysts and reaction conditions for racemization of
(S)-(ꢀ)-a-methylbenzylamine (1). Our starting point was the
work of Kim and co-workers,11 who reported the preparation of
a Pd nanocatalyst supported on AlO(OH) and its use as an
efficient catalyst for racemization and DKR of amines, even in
the absence of an external source of hydrogen.
Table 1 Racemization of (S)-(ꢀ)-a-methylbenzylamine catalyzed by conditions such as a hydrogen atmosphere. However, these
Pd(AlO(OH))a
protocols also lead to deamination by-products.
In order to circumvent these drawbacks we attempted to use
ammonium formate as an alternative hydrogen source
(Table 2), since it is cheap, readily available, safe and opera-
tionally easier to use in the laboratory compared to a hydrogen
atmosphere.
As depicted in Table 2, addition of ammonium formate
improved racemization rate and selectivity. Addition of 0.5 and
1.0 equivalent of ammonium formate (entries 1 and 2, Table 2)
led to lower enantiomeric excess with higher selectivity when
compared to the results in its absence (Table 1, entries 1 and 2).
When catalyst loading of 5 mol% was used, an ee of 32% was
observed aer only 1 h (Table 2, entry 7) and complete race-
mization was observed aer 3 h (Table 2, entry 8), though large
amounts of by-products arose.
Entry
Amount of catalyst (mol%)
t (h)
Sel.a (%)
ee (%)
1
2
3
1
5
5
5
1
3
88
73
19
>99
93
2
a
See Experimental section for details.
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Table 2 Racemization of (S)-(ꢀ)-a-methylbenzylamine catalyzed by
The effect of adding ammonium formate was found to be
greater for racemization catalyzed by Pd on BaSO4 than for Pd
nanocatalyst entrapped in AlO(OH). When the former was used
without any source of hydrogen no racemization occurred even
aer 12 h (entry 1, Table 3), even with catalyst loading as high as
30 mol%. On the other hand, almost complete racemization
was achieved aer only 3 h in the presence of ammonium
formate (entry 2, Table 3), thus indicating a fundamental role of
this reductant in the racemization process. Decreasing
temperature improved selectivity (entry 3, Table 3), leading to
an ee of 3% aer 2.5 h with loss of only 4% of amine. Decreasing
catalyst loading resulted in longer reaction time and lower
selectivity (entries 5 and 6, Table 3). Complete racemization was
also achieved when Pd/CaCO3 and Pd/C were used as catalyst,
but selectivity was only moderate for the former (Table 3, entry
7) and very poor for the latter (Table 3, entry 8).
The next step comprehended in chemoenzymatic dynamic
resolution involving combining the lipase kinetic resolution
mediated by Novozyme 435 and the ammonium formate-assis-
ted racemization process reported above. In spite of the good
results obtained for the racemization reaction, dynamic kinetic
resolution gave conversions lower than expected even for
kinetic resolution aer 12 h (see Experimental section), as
depicted in Table 4 (entries 1 to 3). The results obtained when
reactions were performed in a closed vessel system, led us to
suppose that the ammonium formate needed for the racemi-
zation process could be inhibiting lipase, perhaps through the
NH3 or CO2 released in the course of the reaction.
Pd(AlO(OH)) with ammonium formate
Catalyst
(mol%)
Ammonium formate
(eq.)
t
(h)
Sel.
(%)
ee
(%)
Entry
1
2
3
4
5
6
7
8
1
1
1
1
1
1
5
5
0.5
1.0
1.0
1.5
3.0
5.0
1.0
1.0
5
5
5
5
5
5
1
3
76
78
90
92
94
88
75
34
55
42
61
42
87
95
32
1
On the other hand, increasing the amount of ammonium
formate to 3 or 5 eq. did not improve efficiency or selectivity
(entries 5 and 6, Table 2). This result is in agreement with
previous works of Parvulescu and co-workers.9b These authors
reported that when they used hydrogen as the reducing agent,
high ee in Pd catalyzed racemizations are observed, probably by
suppressing imine formation.
The nature of the support is known to strongly affect both
the activity and selectivity of heterogeneous Pd catalysts in
racemization reactions.9b,c Thus, in the search for a more
selective reaction, we decided to study other heterogeneous Pd
catalysts, such as Pd/BaSO4, which has been reported to be
useful for amine racemization reactions.9b These data are
present in Table 3.
By changing the reaction system to a closed vessel linked
with a gas bubbler we could successfully perform DKR with 30
mol% of Pd/BaSO4, 1.5 eq. of ammonium formate and methyl
methoxyacetate as acyl donor with conversions of 94% and ee of
99% aer 12 h (Table 4, entry 4). The remaining amine was
detected in about 3% and other 3% was identied as byproduct
(see Experimental section for details). Interestingly, low
conversion (65%) was obtained when the DKR was performed
with 10 mol% of Pd/BaSO4, even with reaction time as long as 21
h and using a gas bubbler (see Experimental section for details).
Table 3 Racemization of (S)-(ꢀ)-a-methylbenzylamine catalyzed by
different palladium sources with ammonium formate
Table 4 Dynamic kinetic resolution of (+/ꢀ)-a-methylbenzylamine
catalyzed by Novozyme 435, Pd/BaSO4 and ammonium formate as
green hydrogen source
T
Ammonium formate
t
(h)
Sel. ee
Entry Catalyst
(ꢁC) (eq.)
(%)
(%)
1
2
3
4
5
6
7
8
Pd/BaSO4
95
95
70
70
70
70
0
12
3
2.5 96
2.5 90
2.5 89
5
88
76
>99
2
3
0
24
6
1.5
1.5
1.0
1.5
1.5
1.5
1.5
Pd/BaSO4
(mol%)
NOV435
Reaction
time (h)
2
(%)
ee
(%)
Entry
(mg mmolꢀ1
)
1
2
3
4
10
30
30
30
94
94
188
94
12
12
12
12
37
31
43
94
92
90
92
99
83
Pd/CaCO3 70
Pd/C 70
2.5 76
2.5 17
2
1
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(Table 5, entries 2 to 5) a small increase in conversion is
observed without affecting enantiomeric excess of the product.
Although the continuous ow process herein reported still
requires further improvement, it is important to stress that to
the best of our knowledge this is the rst report of dynamic
kinetic resolution of amines under continuous ow conditions.
Conclusion
In conclusion, a new method for dynamic resolution of
(+/ꢀ)-a-methylbenzylamine has been developed by the using
commercially available Pd/BaSO4 as racemization catalyst and
ammonium formate as an alternative and greener reducing
agent, leading to the desired product in excellent conversion
and optical purity. The developed conditions were then applied
in a loop-like continuous ow system where moderate conver-
sion and excellent enantiomeric excess were obtained. The
results presented here can help to expand the scope of dynamic
resolution of (+/ꢀ)-a-methylbenzylamine by compartmentali-
zation of chemical and biocatalyzed steps under continuous
ow, overcoming the drawbacks found in DKRs performed in
batch mode, such as incompatibility of conditions required for
the racemization and enzymatic steps.
Fig. 2 Schematic of the loop continuous flow reactor for the DKR of 1.
With the optimized DKR conditions, we moved to the design
of a continuous-ow system based on a kinetic resolution using
packed bed reactors containing immobilized lipases, as already
published by our group.12 Performing the kinetic resolution
step under continuous ow conditions in a different compart-
ment from the racemization step would allow it to be run at
room temperature and in shorter reaction time, thus avoiding
enzyme activity decrease due to high temperature required for
the racemization step.
Experimental section
General
˚
Toluene was purchased from Vetec and distilled over 3 A
molecular sieves before use. (+/ꢀ)-a-Methylbenzylamine was
purchased from Sigma-Aldrich and distilled and stored under
argon atmosphere. (S)-(ꢀ)-a-Methylbenzylamine was purchased
from Fluka, methyl 2-methoxyacetate was purchased from
Sigma-Aldrich and both were used as received. Immobilized
Candida antarctica lipase B (Novozyme 435) was purchased from
Novozymes and used as received. All Pd catalysts and ammo-
nium formate were purchased from Sigma-Aldrich and used as
received.
Reactions under continuous ow were performed using an
Asia system which consists of a syringe pump, a solid phase
glass column reactor (d ¼ 1.0000 cm2) with adjustable ends and
pipes equipped with lter. All equipment was purchased from
Syrris.
In order to deal with the low solubility of ammonium
formate and the heterogeneous palladium catalyst in the reac-
tion conditions developed for the racemization process, we
decided to use a loop-like reactor. This set-up, depicted in Fig. 2,
presents some important features that can help to deal with the
difficulties mentioned above. In this set-up, the suspended
solids are kept outside the ow reactor with the use of an
appropriate lter, allowing the catalysts to remain separated
during the entire process, under independent conditions
applied in each step (kinetic resolution and racemization).
Conversion and enantiomeric excess were each monitored until
10 hours of reaction in the loop system and the results are
presented in Table 5.
Dynamic kinetic resolution of (+/ꢀ)-a-methylbenzylamine (1)
could be performed with commercially available palladium
catalyst under continuous ow conditions, leading to good
conversion and high ee aer 10 h (entry 5, Table 5). It is
important to note that from 4.5 hours of reaction to 10 hours
Chiral GC analysis was performed on a Shimadzu GC-2010
chromatograph equipped with a FID, an AOC-20i autosampler
and a chiral CP-Chirasil-Dex CB (25 m ꢂ 0.25 mm ID) or a chiral
b-Dex325 (30 m ꢂ 0.24 mm ID) column using hydrogen as
carrier gas. Injector and detector temperatures were set at
220 ꢁC. GC-FID temperature program for 1-methylbenzylamine
(1) using b-Dex325 column: 90 ꢁC |30 min / 180 ꢁC, 40 ꢁC
minꢀ1| 10 min. GC-FID temperature program for a-methyl-
benzylamine (1) using CP-Chirasil-Dex CB column: 90 ꢁC |30
Table 5 Dynamic kinetic resolution of (+/ꢀ)-a-methylbenzylamine
catalyzed by Novozyme 435, Pd/BaSO4 and ammonium formate as
green hydrogen source, under semi-continuous flow conditions
Entry
Reaction time (h)
2 (%)
ee (%) min / 180 ꢁC, 40 ꢁC minꢀ1| 10 min. GC-FID temperature
program for 2-methoxy-N-(1-phenylethyl)acetamideꢁ (2) using
1
2
3
4
5
2.5
4.5
7
8
10
53
64
68
76
77
99
97
96
96
95
ꢁ
ꢁ
CP-Chirasil-Dex CB column: 105 C |9 min / 180 C, 140 C
minꢀ1
Shimadzu GC-MS-QP2010 Plus chromatograph mass spec-
trometer equipped with an AOC-20i autosampler and
| 10 min. GC-MS analysis were performed on a
a
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5-(phenyl)methylpolysiloxane quadrex (29.6 m ꢂ 0.25 mm ID) triuoroacetic anhydride and 5 mL of triethylamine. Conversion
column using helium as carrier gas. Injector temperature was was calculated as C ¼ ees/(ees + eep).
set at 250 ꢁC. GC-MS temperature program: 60 ꢁC |2 min /
280 C, 20 C minꢀ1| 15 min.
ꢁ
ꢁ
Dynamic kinetic resolution of rac-a-methylbenzylamine
Conversion in the DKR experiments was determined
according to the following formula: [(a-methylbenzylamine
peak area at specied reaction time/internal standard peak
area)/(a-methylbenzylamine peak area before reaction/internal
standard peak area)] ꢂ 100.
Dynamic kinetic resolutions were performed in toluene (3 mL)
with (+/ꢀ)-a-methylbenzylamine (39 mL, 0.3 mmol), 5% Pd
supported on BaSO4 (see Table 4), molecular sieves (375 mg),
Na2CO3 (12 mg), ammonium formate (30 mg, 1.5 eq.), NOV435
(30 or 60 mg; 94 or 188 mg mmolꢀ1 of substrate), methyl
methoxyacetate (68 mL, 0.6 mmol) and biphenyl (30 mg) as
internal standard. Reactions were carried out in closed 4 mL
vials (equipped or not with a gas bubbler) heated at 70 ꢁC in
silicon carbide plates. Aliquots of 300 mL were collected and
diluted in toluene to 1.0 mL for analysis. Enantiomeric excesses
were determined by GC equipped with a chiral column. A GC-
MS was used to identify by-products and to determine the
relative amount of (+/ꢀ)-a-methylbenzylamine, 2-methoxy-
N-(1-phenylethyl)acetamide and reaction byproducts.
Selectivity in the racemization experiment was determined
according to the following formula:
%S ¼ [(Ambatn/Aistn)/(Ambat0/Aist0)] ꢂ 100
Ambatn is the peak area of a-methylbenzylamine of a sample
collected at the reaction time tn. Aist1 is the peak area of internal
standard a sample collected at the reaction time tn. Ambat0 is
the peak area of a-methylbenzylamine of a sample collected
before the beginning of the reaction. Aist0 is the peak area of
internal standard in a of a sample collected before the begin-
ning of the reaction.
Dynamic resolution under continuous ow conditions
A solution of rac-a-methylbenzylamine (390 mL, 3.2 mmol) and
methyl 2-methoxyacetate (640 mL, 6.4 mmol) in toluene (15 mL)
was poured into an Erlenmeyer containing Pd/BaSO4 (900 mg,
0.48 mmol of Pd), Na2CO3 (60 mg) and molecular sieves (1.875
g) at room temperature and connected to a bed packet reactor
lled with NOV435 (700 mg; volume ¼ 1.9635 cm3) through a
pipe equipped with a lter. The solution was pumped through
the bed packet reactor at a rate of 250 mL minꢀ1 (corresponding
to residence time of 7.9 min) at room temperature. Aer 70
minutes ammonium formate (150 mg, 1.6 mmol) was added to
the Erlenmeyer, which was heated to 70 ꢁC while the bed packet
reactor lled with NOV435 remained at room temperature. The
solution was allowed to ow through the closed system
composed of the bed packet reactor and Erlenmeyer for 10 h.
Aliquots of 300 mL were collected and diluted in toluene to 1.0
mL for analysis. Enantiomeric excesses were determined by
GC equipped with a chiral column. A GC-MS was used to
identify by-products and to determine the relative amount of
(+/ꢀ)-a-methylbenzylamine, 2-methoxy-N-(1-phenylethyl)acet-
amide and reaction byproducts.
Synthesis of (+/ꢀ)-2-methoxy-N-(1-phenylethyl)acetamide (2)
A solution of racemic (+/ꢀ)-a-methylbenzylamine (0.24 mmol)
and methyl 2-methoxyacetate (0.96 mmol) in toluene (3 mL) was
stirred at 70 ꢁC for 24 h. The reaction media was washed with a
10% aqueous solution of HCl and dried over Na2SO4. An aliquot
of 300 mL was collected, diluted in 700 mL of toluene and directly
analyzed by GC-MS spectrometer and used for optimization of
chiral GC-FID temperature program.
General procedure for racemization reactions
Racemization reactions were performed in toluene (3 mL) with
(S)-(ꢀ)-a-methylbenzylamine (39 mL, 0.32 mmol), palladium
catalyst (see Tables 1 and 2), Na2CO3 (12 mg), molecular sieves
(375 mg), ammonium formate (see table) and biphenyl (30 mg)
as internal standard. Reactions were carried out in 4 mL vials
heated at 70 ꢁC or 95 ꢁC in silicon carbide plates. Aliquots of 300
mL were collected, diluted in toluene to 1.0 mL and analyzed
aer derivatization with 5 mL of triuoroacetic anhydride and 5
mL of triethylamine. Enantiomeric excesses were determined by
GC equipped with a chiral column.
Acknowledgements
The authors thank FAPERJ, CNPq, CAPES and FINEP for
Kinetic resolution of (+/ꢀ)-a-methylbenzylamine
nancial support.
Kinetic resolution reactions were performed in toluene (3 mL)
with rac-a-methylbenzylamine (39 mL, 0.32 mmol), methyl 2-
methoxyacetate (68 mL, 0.64 mmol), molecular sieves (375 mg),
Na2CO3 (12 mg), immobilized Candida antarctica lipase B
(NOV435, 30 mg, 94 mg mmolꢀ1 of substrate) and ammonium
formate (see table). Reactions were carried out in closed 4 mL
vials heated at 70 ꢁC in silicon carbide plates. Aliquots of 300 mL
were collected, diluted in toluene to 1.0 mL and analyzed by GC
directly for ee of product (eep). The ee of substrate (ees) was
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