Rediscovering aminal chemistry: Copper(ii) catalysed formation under mild conditions

Article abstract of DOI:10.1039/d0gc01977a

Aminals, the N,N analogues of acetals, have been thoroughly explored in organic chemistry, with a particular focus on heteroaromatic aldehyde lithiation. Nevertheless, the existing methodologies for their formation typically employ harsh conditions limiting their usefulness. In this work, we present an efficient and mild methodology for the preparation of aminals from aromatic aldehydes, including furanic platforms. These mild conditions allowed ease of access to a plethora of aminals and as such we set out to explore previously unaccessible potential applications. By studying the stability of various aminals, we were able to develop a simple aldehyde protecting group based on a commercial diamine which is deprotected under mind conditions. We developed a protocol for the scavenging of genotoxic aldehydes by taking advantage of our methodology and a diamine resin, as well as early studies on the development of a stimuli-responsive release system using a salycil aldehyde derived aminal. This journal is

Full text of DOI:10.1039/d0gc01977a

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DOI: 10.1039/D0GC01977A
ARTICLE
Rediscovering aminal chemistry: Copper (II) catalysed formation
under mild conditions
Juliana G. Pereira,a João P. M. António,a Ricardo Mendonça,b Rafael F. A. Gomes*a and Carlos A. M.
Received 00th January 20xx,
Accepted 00th January 20xx
Afonso*a
DOI: 10.1039/x0xx00000x
Aminals, the N,N analogues of acetals, have been thoroughly explored in organic chemistry, with a particular focus on
heteroaromatic aldehyde lithiation. Nevertheless, the existing methodologies for their formation typically employ harsh
conditions limiting their usefulness. In this work, we present an efficient and mild methodology for the preparation of
aminals from aromatic aldehydes, including furanic platforms. These mild conditions allowed ease of access to a plethora of
aminals and as such we set out to explore previously unacessible potential applications. By studying the stability of various
aminals, we were able to develop a simple aldehyde protecting group based on a commercial diamine which is deprotected
under mind conditions. We developed a protocol for the scavenging of genotoxic aldehydes by taking advantage of our
methodology and a diamine resin, as well as early studies on the development of a stimuli-responsive release system using
a salycil aldehyde derived aminal.
preparation of rotenoid deguelin17 (Figure 1B) and recent
reports by Maulide and co-workers show an elegant use of
aminals as reagent for hydroaminomethylation of unactivated
alkenes/ynes18 (Figure 1C).
The current literature endorses the possibility of, among other
applications, using aminals as an aldehyde protection group.
However, the commonly used harsh conditions11–14,19,20 that
usually precede the formation of aminals may be responsible
Introduction
The carbonyl group has been thoroughly studied in synthetic
organic chemistry.1 Due to the importance of this group, various
methodologies for its selective protection have been
developed. Amongst several protection groups, the acetal is the
most commonly used.1 Acetals can be prepared under various
conditions, although most methods rely on acid catalysis and/or
harsh conditions.2
We have been involved in the valorisation of biomass derived
furanic platforms, such as furfural and 5-hydroxymethylfurfural
(HMF)3–5. These aldehydes are sensitive both to acid and
temperature6 and in course of our studies we observed that
protection of HMF’s aldehyde with ethylene glycol promoted by
para-toluenosulfonic acid (pTSA) lead to the formation of
homo-acetals and insoluble humins7.
On the other hand, aminals, the N,N analogues of acetals,8,9
have been prepared from furfural as intermediate in the
preparation of chlorinated furan aldehydes that were
incorporated in pyrazolopyrimidinedione as Helicobacter pylori
glutamate racemase inhibitors (Figure 1A).10 These aminals,
commonly obtained by refluxing the corresponding aldehyde
with a diamine (e.g. in benzene),11–14 underwent aminal
directed lithiations aiming at the preparation of intermediates
in the synthesis of natural products such as the aporphinoid
alkaloids15 and Cichorine16, among others. Knovanaegel
condensation using dimorpholino aminal has been used for the
for its lack of usage by organic chemists.
Selected examples of reported reactions that required the aminal group:
S
O
H
O
Me
Halogenation
Cl
Basarab et al (
A.
2008
)
OMe
O
MeO
Knoevenaegel
condensation
NRR'
NRR'
aminal
NHRR'
OH
O
O
H
(het)Ar
benzene
or toluene
reflux
Me
Me
O
O
Harsh conditions
B.
2013
)
Scheidt et al (
Low yields
No consistent study
on aminal stability
Hydroamino
methylation
Me
N
Ph
C.
O
H
2019
N. Maulide et al (
)
(het)Ar
H
This work:
Mild preparation in water
High yields
Stability studies / Reaction
compatibility
Aldehyde scavanger
Stimuli-responsive dynamic
bond
NHRR'
NRR'
NRR'
Cu(OTf)2 (0.1 mol %)
H2O, r.t., 2 min
(het)Ar
aminal
Figure 1. General method for the preparation of aminal group
and disadvantages, selected examples of key reactions
requiring aminal group.
a. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy,
Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003, Lisbon
(Portugal).
b. Hovione FarmaCiencia SA, Sete Casas; 2674-506 Loures, Portugal
E-Mail: rafael.gomes@campus.ul.pt, carlosafonso@ff.ulisboa.pt
Although emerging green technologies such as the reduction of
CO2 under hydrosilylation conditions to aminals,21 the lack of
mild and efficient methodologies for a broad preparation of
Electronic
Supplementary
Information
(ESI)
available
online.
See
DOI: 10.1039/x0xx00000x
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ARTICLE
O
aminals and the possibility of using them as protection group of
acid labile furanic platforms lead us to study their formation in
aqueous media and in the presence of Lewis Acid catalysts,
avoiding the need of hazardous organic solvents and
stoichiometric additives.
Herein, we develop a mild methodology to prepare aminals
under more sustainable conditions and showcase their
relevance as 1) an aldehyde protection group; 2) a scavenger of
potential genotoxic impurities under continuous flow
conditions; and 3) a stimuli-responsive group for the release of
diamines/aldehydes.
View Article Online
DOI: 10.1039/D0GC01977A
O
N
H
O
N
O
O
cat
H2O
H
N
furfural
O
rt, 2 min
1
Entry
Cat (0.1 mol%)
none
FeCl3 6H2O
CuSO4 5H2O
CuCl2 2H2O
1 (%)b
Conversion (%)b
1
2
3
0
0
0
0
.
100
100
81
.
.
4
0
5
6
7
8
Dy(OTf)3
Zn(OTf)2
Sc(OTf)3
TfOH
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
0
0
0
81
90
100
98
Results and discussion
Our initial aim was the development of a methodology to
prepare aminals under mild conditions that would not cause
decomposition of furan aldehydes. As such, we started this
work by reacting furfural with morpholine to prepare aminal 1.
Wilhelm and co-workers had already reported the formation of
aminals in water although in long reaction times and, in some
cases requires high temperature.22 The use of water as solvent
is appealing due to the reduction of organic solvent waste, so
we initiated a screening of Brønsted and Lewis acids (Table 1) in
water that would promote the reaction. In the absence of a
catalyst no conversion of the aldehyde was observed after 2
minutes (Table 1, Entry 1). Due to the unstable nature of furfural
most Lewis acids lead to the formation of insoluble black tars
with total consumption of the aldehyde (Table 1, Entries 2-7).
Moreover, it has been reported that furfural in the presence of
secondary amines may undergo rearrangement to trans-4,5-
diamino-cyclopent-2-enones (CP)3 and, indeed, we observed
92
9
Quant (96)c
100
100
100
10d
0
97
11e
aReaction conditions: furfural (0.1 mmol), morpholine (0.22 mmol, 2
equiv), cat (0.1 mol%), H2O (0.1 mL). The reaction was stirred for 2
min and extracted with ethyl acetate. bYields determined by 1H-
NMR using 1,3,5-trimethoxybenzene as internal standard. cIsolated
d
yield, 10 g scale. Reaction time is 8h, formation of cyclopentenone.
eAcetonitrile was used as solvent.
Heteroaromatic aldehydes such as furfural and HMF derivatives
afforded the desired aminal product (1-4) in excellent yield.
When using HMF no side products, such as homo-acetals, were
detected. No deprotection of the silyl group neither hydrolysis
of the acetyl ester was observed (3 and 4). The condensation of
morpholine with benzaldehyde afforded the desired aminals in
high yields in the presence of electron withdrawing and electron
donating substituents (5-16), despite the need of using an
excess of amine in the case of electron donating substituents (7
and 8). It is noteworthy that phenols did not impair the
formation of the aminal (8 and 16). However, the formation of
an aminal using 4-(N-dimethylamino)-benzaldehyde in
significant yield was not possible. Reaction with a dialdehyde
such as terephtalaldehyde afforded the mono aminal 15 in 90%
yield which cannot be separated from the diaminal product. It
is noteworthy that some of these aminals may undergo
hydrolysis to some extent in CDCl3.
The scope of amines (17-21) included cyclic amines such as
morpholine, piperidine, methylpiperazine, N,N-methyl-
aminoaniline and diamines. The scope also included
aminoalcohols to form N,O-acetals of benzaldehyde (22 and 23)
and HMF (38). The reaction was not impaired by the presence
of carboxylic acid substituents and proceeded smoothly to
afford imidazolidine 24.
formation
of
CP
as
a
side
product.
When
trifluoromethanosulphonic acid (TfOH) was used, we observed
formation of 81% aminal, but also formation of side products
such as CP (Table 1, Entry 8). Surprisingly, the reaction in the
presence of Cu(OTf)2 afforded the aminal 1 in quantitative
analytical yield after 2 minutes (Table 1, Entry 9). If the reaction
was allowed to stir further 8h, no aminal was detected and was
observed only the corresponding CP (Table 1, Entry 10). The fact
that other copper salts did not afford the aminal but instead,
lead to decomposition highlights the importance of the triflate
anion. The reaction was quite robust to variations of furfural
concentration, with no loss of yield from 0.1 to 4 M. The
reaction using Cu(OTf)2 was scaled up to 10 g, affording 25.5 g
(96%) of the corresponding aminal 1 which precipitates directly
from the aqueous reaction media (Table 1, Entry 9). Acetonitrile
can be an organic alternative to water with the disadvantage
that the product does not precipitate from the reaction media.
Nevertheless, posterior addition of water causes the
precipitation to occur (Table 1, Entry 11). With the optimized
conditions in hands, we extended the methodology by using
different aromatic aldehydes and amines (Scheme 1).
Formation of hexahydropyrimidines from different ortho-
substituted aldehydes was not significantly impaired despite
the electronic and steric effects (26-32).
Table 1. Reaction optimizationa
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J. Name., 2013, 00, 1-3 | 2
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DOI: 10.1039/D0GC01977A
ARTICLE
NHR2
NR2
O
(het)Ar
(het)Ar
Cu(OTf)2 (0.1 mol%)
NR2
H
H2O (4 M)
rt, 2 min
O
N
O
O
O
O
O
N
N
N
N
N
N
N
O
O
O
O
N
N
HO
N
AcO
N
TBSO
O
O
O
N
O
O
O
Me
a
1
2
3
4
5
6
, 98%
, 96%
, 94%
, quant
, quant
, quant
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
MeO
HO
F
Cl
Br
F3C
b
b
7
8
9
10
11
12
, 95%
O
, 96%
O
, quant
O
, quant
O
, 98 %
N
, 94%
Me
N
N
N
N
OH N
N
N
N
N
N
N
N
O
O
O
O
O
O2N
NC
OHC
N
Me
c
13
14
15
16
17
18
, quant
, quant
N
, quant
, 90%
Ph
, quant
, quant
N
Me
OH
Me
Me
Pr
Me
Me
N
N
N
N
N
O
N
Me
N
Me
N
Me
N
N
Me
HO
Me
HO2C
24
, quant
25
19
20
21
22
23
, quant
, 94 %
, quant
, 90%
, 98%
, 94%
Me
Me
OH
Me
OH
Me
OH
Me
NO2
Me
Br
Me
OMeN
N
N
N
N
N
Cl
N
N
Me
N
Me
N
Me
N
Me
N
Me
N
Me
N
Me
NO2
OMe
26
27
28
29
30
31
32
, quant
, 96%
, 89%
, 87%
, 90%
, 86%
, 92%
Me
N
Me
Me
Me
Me
Pr
N
N
N
N
N
N
N
O
O
O
O
O
O
N
Me
HO
N
Me
HO
N
Me
HO
O
HO
N
HO
Me
N
Me
35
36
37
38
, 95%
33
34
, 98%
, quant
, quant
, quant
, quant
Scheme 1. Aldehyde and amine scope for the preparation of aminals. Reaction conditions: aldehyde (2.0 mmol), amine (4.0 mmol, 2 equiv or 2.0 mmol, 1
equiv in case of diamines or aminoalcohols), Cu(OTf)2 (0.1 mol%), H2O (0.5 mL). aReaction peformed in 10 gram scale. b4 equiv of morpholine were used. c5
equiv of N-Methyl-piperazine were used.
1
In order to select the aminal most suited to be used as established by quantitative H-NMR in D2O buffer using a co-
protection group, we performed an initial stability assay in axial probe containing 1,3,5-trimethoxybenzene as internal
aqueous media. The stability to hydrolysis in water was standard. HMF-derived aminals were selected due to their
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Green Chemistry
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A. Deprotection of aminal 36
higher solubility in D2O in relation to the corresponding
benzaldehyde derivatives. First, we accessed the stability at pH
7 (Figure 2A), and we observed that aminal 2, 35 and 38,
prepared from morpholine, N-propyl-aminoalcohol and N,N’-
methyl ethylenodiamine respectively, reverted to the aldehyde
upon first 1H-NMR measurement (roughly 3 minutes). The
hexahydropyrimidine 36 reverted to 60 % aldehyde in 10 hours,
upon which no more hydrolysis was observed even after 25
hours. The aminal prepared from N,N’-dimethyl-α-aminoaniline
34 did not revert to the aldehyde during 25 hours. We studied
the stability of 36 at higher pH (Figure 2, B) and observed that
at pH 8 the equilibrium is reached at 40% aldehyde after 20h
and at 18% after 10h at pH 9. The aminal 34 remained stable
under acidic (pH 4.5) and basic (pH 9 and pH 12) conditions
(Figure 2B).
View Article Online
Me
N
DOI: 10.1039/D0GC01977A
O
AcOH (2 eq)
O
O
THF:H2O
rt, 1h
HO
N
HO
H
Me
36
HMF,
97%
B. Selected examples of reactions in the presence of aminal 36 or 21
NaBH4 (1 equiv)
MeOH, 0ºC to rt, 1h
O
OH
36
36
H
H
36
no conversion of
O2N
O2N
39
, 91%
PhMgBr (2 equiv)
THF, 0º C - rt, 12h
OH
O
H
36
no conversion of
40
, 70%
Me
(1 equiv)
H2N
Ideally a protection group should be selectively deprotected
under mild conditions. While we observed that aminal 34 is the
most stable amongst the studied aminals and N,O-acetals,
unfortunately, the hydrolysis of 34 under acidic conditions
(pTSA or HCl aq) was not successful (See Supporting Information
for complete details on the deprotection attempts). As such, we
moved our focus to aminal 36. Gratefully, acetic acid in a
THF:H2O mixture (Scheme 2A) was able to hydrolyse 36 to the
free aldehyde. We opted not to explore the N-substituent of the
diamine since aminal 36 is prepared from readily available
commercial N,N′-dimethyl-1,3-propanediamine. Exploring the
selected HMF aminal 36, we assessed the robustness of this
protecting group under 1) reduction conditions; 2) amidation
conditions; 3) presence of strong nucleophile; 4) oxidative
conditions (Scheme 2B). The reduction of 4-nitrobenzaldehyde
by NaBH4 was not impaired by the presence of 36, affording the
corresponding 4-nitrobenzylic alcohol in 91% isolated yield. As
such, we can use the aminal as protection group under
reductive conditions. Only when large excess of NaBH4 was
used, a side product formed by the reduction of 36 was
detected. The addition of a Grignard reagent such as PhMgBr to
benzaldehyde afforded the corresponding alcohol in 70%
isolated yield.
DCC (1 equiv)
DMAP (0.1 equiv)
DCM, rt, 12h
O
O
Me
36
N
OH
H
36
no conversion of
41
, 47%
Me
O
PCC (1.5 equiv)
DCM, rt, 4h
OH Me
Me
21
Me
21
no conversion of
Me
Me
42
, 74%
C. Methylation of furfural via lithiation of the furan ring in the presence of an
acetal and aminal protection group.
1. nBuLi, TMEDA
THF, -78ºC, 2h
2. MeI, 20º C, 12h
3. HCl (aq.)
1. nBuLi, TMEDA
THF, -78ºC, 2h
2. MeI, 20º C, 12h
3. HCl (aq.)
Me
O
O
N
O
O
O
Me
O
N
H
82% yield
no reaction
Me
43
Scheme 2. A. Deprotection of aminal 36 under mildly acidic conditions; B.
Selected examples of common reactions in the presence of aminals:
Reduction; Grignard addition; Steglich coupling; PCC oxidation (from top to
bottom); C. Methylation of furfural via lithiation of the furan ring in the
presence of an acetal and aminal protection group.
No side products of the addition of the nucleophile to the
aminal or the corresponding HMF aldehyde were detected.
Acetals have been used to protect aldehydes during amidations
with primary amines.23,24
We observed that benzoic acid underwent Steglich coupling
with pentylamine successfully in the presence of 36. The
corresponding HMF imine was not detected. The amide was
obtained in 47 % isolated yield. Oxidation of (-)-menthol to (-)-
menthone using pyridinium chromium chloride (PCC) in the
presence of benzaldehyde protected aminal 21 was successful,
with no formation of oxidation side products of the aminal
group. Mentone was obtained in 74% isolated yield.
In an attempt to methylate position 5 of furfural we performed
a tandem lithiation-methylation of acetal protected and aminal
protected furfural. Using n-BuLi as lithiating agent and MeI as
electrophile no reaction was observed for acetal protected
furfural. Differently, the aminal protected furfural underwent
methylation and we were able to reproduce the reported
conditions25 affording 5-methylfurfural 43 in 82% yield.
R1
O
N
D2O Buffer
O
O
HO
H
HO
X
X = NR1, O; R1 = alk, (Ci = 0.10 M)
HMF
B. Stability at pH 4.5 - 12
A. Stability at pH 7
12
6
4
2
0
10
8
6
4
2
0
0
5
10
15
20
25
0
20
40
60
80
Time (h)
2, 35, 38 36
Time (h)
34
36, pH 8
36, pH 9


34, pH 4.5, 9 and 12
Figure 2. Stability assays for the hydrolysis of HMF aminals in D2O. Starting
concentration is 0.1 M; A. represents the formation of HMF at pH 7 for
aminals 2, 34, 35, 36, and 38; B. represents the formation of HMF at pH 8 and
9 for aminal 36 and at pH 4.5, 9 and 12 for aminal 34.
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
absence of catalyst the resin was only able to retaiVnie7w0Ar%ticleoOf ntlhinee
DOI: 10.1039/D0GC01977A
aldehyde (Table 2, Entry 4).
SH
API
CO2H
SH
API
O
H
NH2
H
NH2
Table 2. Optimization studies for the scavenging of aldehydesa
R
N
HO
HO
NH2
NH
Cu(II)
Genotoxic impurity
CO2H
Pure API
API from the reaction
mixture
O
H
H
O
H
N
N
R
R
NH2
R
Genotoxic impurity
trapped as aminal
Cu(OTf)2 (0.1 mol%)
aldehyde
recovered
aldehyde
EtOH:H2O (0.1 M)
Scheme 3. Strategy for the removal of genotoxic aldehyde impurities.
348 L, 69.6 L.min-1 r.t.
When preparing active pharmaceutical ingredients (API) there
is concern of impurities that can be formed during the
preparation/storage of the API. The impurities are highly
regulated due to the toxicity or unknown toxicity profiles that
may lead to undesired side effects when the API is
administered. Aldehydes are amongst the possible genotoxic
impurities due to their electrophilicity and are considered highly
reactive.26 In some cases the calculated risk of the aldehyde is
enough for action to be taken in order to actively remove the
aldehyde used as starting material or to find an alternative path
altogether.27 Nevertheless, studies point towards the need to
actively remove the genotoxic instead of rearranging an
alternate synthetic route.28 Amine resins have been used for the
removal of aldehydes from Grignard addition reactions, by the
formation of an imine.29 This methodology is not always
efficient and involves stirring the resin in the reaction mixture
for long periods of time to remove the aldehyde. We envisioned
that under our conditions, the formation of aminals with resin
supported diamines can be used as strategy for the removal of
aldehydes from reaction mixtures in a continuous flow system
(Scheme 3).
Aldehyde input
(mmol)/(M)
Scavenged
aldehyde (%)
Entry
R
1
2
3
4b
5
6b
H
H
H
H
OMe
0.035/0.1
0.002/0.002
1/1
quant
quant
97
70
93
1/0.1
1/0.1
1/0.1
OMe
40
aReaction conditions: benzaldehyde (0.035 mmol), ethanol:H2O (0.35 mL,
1:1), Cu(OTf)2 (0.1 mol %), resin (Sigma Aldrich: 472093; 395 mg, 4-5.7
mmol/g). Benzaldehyde measured by HPLC; bReaction in absence of
Cu(OTf)2
This result is even more noticeable in the presence of electron
rich aldehydes, such as 4-methoxybenzaldeyde (PMB), where
only 40 % of the aldehyde is captured in the absence of catalyst
(Table 2, Entry 6), comparing with 93 % in the presence of 0.1
mol % Cu(OTf)2 (Table 2, Entry 5).
Next, we extended the scope of our system by performing two
sets of reactions in the presence of multiple aldehydes and
analysed the recovered aliquots by HPLC. The first set was
carried out with benzaldehyde and derivatives containing
electron-withdrawing substituents, furfural and HMF (Scheme
4, top) and the complete removal of the aldehydes from the
initial solution was successful.
We started this study by packing a small HPLC column with
commercial polymer-bond ethylenediamine resin (Sigma
Aldrich: 472093), containing 4-5.7 mmol/g diamine, and reacted
a
benzaldehyde and Cu(OTf)2 (0.1 mol %) solution in
ethanol/water (1:1) with a residence time of 5 minutes (Table
2, Entry 1). We analysed the aliquots after the mixture reacted
with the diamine resin by HPLC and no aldehyde was detected.
Ethanol was selected as co-solvent due to the industrially
friendly properties. The scavenging is equally efficient in a
mixture of ethanol/water 9:1 and by replacing the ethanol for
methanol (results not shown). Increasing the residence time to
10 minutes and 1 hour did not impact negatively the
scavenging.
The second set of aldehydes corresponded to the electron rich
aryl aldehydes, which were inherently less prone to react with
the resin. Indeed, after feeding the reactor with 0.1 mmol of
aldehydes we recovered 0.2 % and 0.08 % of naphtaldehyde and
4-methylbenzaldehyde respectively (Scheme 4, bottom).
These results demonstrate this system’s ability to remove
aldehydes from complex mixtures and its potential industrial
application as an API impurity scavenger.
O
Moreover, we observed that either decreasing or increasing the
O
H
H
O
N
R
no aldehyde
R
NH2
concentration of benzaldehyde to 0.2 mM and
1
M,
H
R = H
R = CH2OH
R = H
R = Br
R = CHO
respectively, does not significantly affect the resin efficiency
(Table 2, Entry 2 and 3). The ability of our system to remove
aldehydes in small concentration highlights its potential as an
industrial impurity scavenger. The saturation of the resin with
benzaldehyde was studied by continuously feeding the system
with a benzaldehyde 1 M solution. We observed that the system
(395 mg resin) was able to efficiently scavenge 1 mmol of the
aldehyde (Table 2, Entry 3), after which the resin is no longer
capable of capturing more aldehyde. This result shows the
efficiency of the system considering the diamine content of the
resin, which corresponds to 1.6 – 2.2 mmol diamine. In the
Cu(OTf)2 (0.1 mol%)
EtOH:H2O (1:1, 0.1 M)
348 L, 69 L min-1 , r.t.
O
O
H
O
H
O
H
H
N
NH2
R
H
R = 2-OH
R = 4-OMe
R = 4-Me
Cu(OTf)2 (0.1 mol%)
EtOH:H2O (1:1, 0.1 M)
348 L, 69 L min-1 , r.t.
Me
naphtCHO, 0.2 % PMB, 0.08 %
Scheme 4. Scavenging of aryl aldehydes. Electron poor aryl aldehydes and
furyl aldehydes on top; Electron rich aryl aldehyde and naphtaldehyde on
bottom.
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0.6
0.4
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DOI: 10.1039/D0GC01977A
Stimuli-responsive systems have been thoroughly studied and
applications have been described in material sciences,31
catalysis32 and medicinal chemistry.33 This response may appear
in the form of an olefin isomerization, rotation or even the
breaking/formation of covalent bonds and can be caused by
light,34 redox conditions35 or pH stimuli.33
Due to the reversible nature of aminals we set out to study a
proper system that could be employed for stimuli responsive
release. We envisioned that ortho substituents would have a
major impact on the aminal stability, in particular a phenol
group could destabilize the aminal by intramolecular acid
catalysis. We started by assessing the rates for the hydrolysis of
six ortho substituted aminals by UV-Vis spectroscopy under
highly diluted conditions (Figure 4A). Much to our delight by
plotting the obtained kobs and the parameters for the electronic
effects (σpara, Figure 4B) and steric effects (Taft σ*, Figure 4C)
we observe that: 1) electronic effects overruled the steric
effects; 2) electron donating groups stabilize the aminal; 3) the
phenol is an outlier to the correlation, being drastically less
stable. This findings suggest a different mechanism for the
hydrolysis of the aminal such as our hypothesis of
intramolecular acid catalysis. Moreover, introduction of
additional substituents on the ortho phenol aldehyde (Scheme
1, 31 and 32) did not cause significant alteration of stability.
1
2
3
4
5
Reutilization cycle
Scavenged
Recovered
Figure 3. Scavenging and recovery of benzaldehyde utilizing the resin system
and washing with 1 M HCl.
Finally, we attempted to recover the scavenging potential of the
resin by acidic treatment, promoting hydrolysis of the aminal,
followed by basic treatment to deprotonate the ammonium
salts. Gratefully, we were able to recover 88 % of the scavenged
aldehyde by washing the resin with a 1 M HCl solution (Figure
3). The washed resin then regained the ability to capture
aldehyde. The procedure was repeated five times, although in
each reutilization more HCl solution was required to wash the
aldehyde. Acetic acid (1M) was also efficient at recovering the
aldehyde and, as such, is a viable alternative for HCl solution.
As previously discussed, the removal of genotoxic aldehyde
intermediates is a crucial process in the synthesis of APIs. One
such example corresponds to the preparation of AZD 9056, a
small molecule studied for treatment of Rheumatoid Arthritis,
whose preparation involves a reductive amination of the
corresponding AZD 9056 aldehyde (Scheme 5A).28,29 This
aldehyde remains as a genotoxic impurity downstream in the
production process due to its low volatility. Therefore, it is
necessary to use complex, and often inefficient, processes to
remove it. We envisioned that our system could be successfully
employed to overcome this problem. To study the efficiency of
our system in this particular case, we prepared model
aminoalcohol 44 by reductive amination of 3-phenylpropanal
(PPA). Using our optimized conditions, we fed the reactor with
a mixture of PPA and 44 in a 1:1 ratio and, after evaporating the
output of the reactor, we obtained 100 % of pure 44 (Scheme
5B).
Me
Me
OH
Me
Me
Me
Br
Me
Cl N
A
H
N
OMeN
N
NO2
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
27
28
para = 0.23
29
para = 0.23

= 2.96

21
para = 0
30
26
para = -0.37

para = 0.78

Taft

para = -0.268

Taft

Taft
= 4.25
Taft
= 2.84 Taft


= 0.49
= 0.62
Taft
= 1.34



B
C
OH
outlier
OH
outlier
NO2
Br
Cl
NO2
BrCl
H OMe
OMe
Figure 4. A. Aminals bearing different ortho groups used in the stability study;
B. Hammett plot for the hydrolysis of the selected aminals; C. Steric effect
evaluating by plotting kobs and σ*.
A. Preparation of AZD 9056 HCl salt from genotoxic aldehyde
HCl
These encouraging results indicate that aminals can potentially
be employed as responsive linkers in specific applications such
as material devices and drug delivery systems by using a
protected ortho-phenol aminal with increased stability that
upon phenol deprotection undergoes hydrolysis (100 fold
increase in kobs OH vs OMe).
H
O
N
OH
OH
1) H2N
2) H2/Pt
H
H
N
N
O
Cl
3) HCl, iPrOH
O
Cl
AZD 9056 genotoxic aldehyde
AZD 9056 HCl salt
B. Removal of aldehyde from mixture with AZD model amino alcohol 44
Conclusions
O
In conclusion we were able to develop a mild methodology for
the preparation of aminals from aryl aldehydes and secondary
amines /aminoalcohols. The condensation is catalysed by low
amounts of Cu(OTf)2, 0.1 mol %, in water at ambient
temperature. The reaction is broad in scope for amines and
H
PPA (1 equiv)
H
N
N
NH2
OH
H
N
44
pure
Cu(OTf)2 (0.1 mol%)
EtOH:H2O (1:1, 0.1 M)
348 L, 69 L min-1 , r.t.
OH
44
(1 equiv)
Scheme 5. A. AZD 9056 HCl preparation from genotoxic aldehyde; B. Removal
of PPA from a PPA:44 mixture.
aldehydes.
Hydrolysis
studies
revealed
that
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G. S. Basarab, P. J. Hill, A. Rastagar and P. J. HV. iWeweAbrtbicolerOnn,line
Bioorg. Med. Chem. Lett., 2008, 18,D4O71I:610–.41702392/.D0GC01977A
hexahydropyrimidines are the most appropriated for use as
protection group of aldehydes. The hexahydropyrimidine
withstood several reaction conditions such as reductive,
oxidative, basic and amidation conditions and was deprotected
with ease using acetic acid.
On the other hand, the use of a diamine resin allowed the
scavenging of aldehydes that can be present as genotoxic
impurities in APIs using our copper triflate methodology. The
captured aldehydes can be recovered by acidic treatment of the
resin. Finally a study on ortho substituents on the aryl aminal
revealed that phenol moiety destabilize the aminal and is an
outlier upon plotting electronic parameters vs rates of
hydrolysis. These results suggest that one can explore this
function as a stimuli-responsive system through a selective
deprotection of a phenol group therefore inducing the phenol
catalysed hydrolysis of the aminal.
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Conflicts of interest
There are no conflicts to declare.
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