Towards a sustainable synthesis of aniline-derived amides using an indirect chemoenzymatic process: Challenges and successes

Article abstract of DOI:10.1039/c3ra46499g

A general, catalytic and sustainable synthesis of amides has been targeted which utilises a chemoenzymatic step to generate an activated amide coupling partner in situ. A screen of a series of known activating agents was performed and the successful agents taken forward to determine their utility in such a one-pot enzyme-catalysed process. In these studies, a new chemoselective reagent ((isopropylideneamino) 2-phenylacetate) has been identified, which demonstrates excellent selectivity for the acylation of primary anilines over secondary anilines, unlike the more conventional acid chloride equivalent, which is unselective. The development of a chemoenzymatic synthesis of 2-hydroxyethyl benzoates (ethylene glycol mono-benzoate esters) has also been achieved.

Full text of DOI:10.1039/c3ra46499g

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Towards a sustainable synthesis of aniline-derived
amides using an indirect chemoenzymatic process:
challenges and successes†
Cite this: RSC Adv., 2014, 4, 1609
*
Samridhi Lal and Timothy J. Snape
A general, catalytic and sustainable synthesis of amides has been targeted which utilises a chemoenzymatic
step to generate an activated amide coupling partner in situ. A screen of a series of known activating agents
was performed and the successful agents taken forward to determine their utility in such a one-pot
enzyme-catalysed process. In these studies, a new chemoselective reagent ((isopropylideneamino) 2-
phenylacetate) has been identified, which demonstrates excellent selectivity for the acylation of primary
anilines over secondary anilines, unlike the more conventional acid chloride equivalent, which is
unselective. The development of a chemoenzymatic synthesis of 2-hydroxyethyl benzoates (ethylene
glycol mono-benzoate esters) has also been achieved.
Received 7th October 2013
Accepted 18th November 2013
DOI: 10.1039/c3ra46499g
www.rsc.org/advances
that such a process can take place, catalytically, whereby the
enzyme is used to catalyse the synthesis of an activated acyl
Introduction
donor followed by an amide forming step which takes place
outside of the active site. Moreover, it was shown that anilines,
which cannot be catalysed directly by the enzyme used (CAL-B),
do react with the activated acyl donor outside of the active site,
thus providing a series of acetanilides.11 However, limitations
exist in the substrate scope of the process developed so far.
Despite the fact that N-acylation reactions are used frequently in
the preparation of drug candidates, the development of a
general, catalytic, environmentally friendly, sustainable and
scalable synthesis of amides remains elusive.1 Nevertheless, due
to their importance, numerous synthetic methods exist to
prepare amides, and many more are continually being devel-
oped;2,3 unfortunately, existing methods are reaching their
inherent limits as they oen involve stoichiometric activating
agents and other coupling reagents or metals, which require
expensive removal and disposal at the end of the reaction, thus
increasing their environmental factor (E factor) and decreasing
their atom efficiency.4 Additionally, more traditional methods
involve toxic, corrosive, and oen unstable acid chlorides or
anhydrides for their preparation.3 Therefore, developing a
method which uses fewer or catalytic reagents and obviates the
need to isolate intermediates would be very desirable to the
synthetic community. Biocatalysis is an ideal green and
sustainable technique to answer this need and many research
groups have attempted to achieve this goal.5–7 Unfortunately,
the limitation in the volume of an enzyme's active site means
that the size of the accepted substrates is somewhat limited too.
This can be partially overcome through the directed evolution of
the enzyme,8–10 or, more simply, if the aminolysis reaction takes
place outside of the active site itself. We have recently shown
Results and discussion
In order for this method to become of value to the synthetic
community, it was necessary to expand the scope of the process
and to determine if alternative acylating agents and activating
agents could be employed to enable access to a wider variety of
amides, but more importantly, those amides which are elusive
through other sustainable biocatalytic means.
Scheme 1 outlines the proposed catalytic cycle being studied
herein, whereby an ester (1) is added to the reaction, which,
through a CAL-B catalysed reaction with known activating
agents (4 – identied by a simple screen of their activity with the
relevant amines or by literature precedent), generates the acti-
vated derivatives 3. The amine (i.e. aniline 5), then reacts with
the activated agent 3 as it leaves the active site, thus producing
the desired product 6 and re-generating the activating agent 4.
Consequently, the reaction can be both catalytic in enzyme
(CAL-B) and the activating agent 4,11 which can be re-used in
subsequent reactions, only producing inert alcohol by-products
2, thus generating a green, sustainable, atom economic and
non-toxic synthesis of amides.
School of Pharmacy and Biomedical Sciences, University of Central Lancashire,
Preston, PR1 2HE, UK. E-mail: tjsnape@uclan.ac.uk; Fax: +44 (0)1772 892929; Tel:
+44 (0)1772 895805
† Electronic supplementary information (ESI) available. CCDC 949891. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra46499g
In order to expand the scope of our previous study,11 towards
a variety of industrially-relevant target amides, attention was
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Scheme 1 Proposed general catalytic cycle.
focussed on varying the activating agents, starting esters and contrast to the results seen previously, where reactions with
target amides, as shown in Fig. 1.
vinyl acetate, acetone oxime and CAL-B, not only gave good
yields of the activated ester (3, R ¼ Me, OACT ¼ 7; 76%), but that
it also reacted cleanly with a variety of eleven different anilines
(41–84%) and benzylamine (62%), and that it was shown to be
chemoselective over S- and O-based nucleophiles and secondary
anilines.11
Alkanoate esters
Initial studies began with a direct continuation of the previous
work, moving away from vinyl esters to more convenient and
synthetically useful methyl alkanoates (13–16, Fig. 1), in the
hope of developing a short sustainable route to new acetanilide
derivatives, such as the tyrosine kinase inhibitor, cabozanti-
nib.21 Unfortunately, under the standard conditions (MTBE (1
M), ester (1 eq.), acetone oxime (0.1–1 eq.), aniline (1 eq.), CAL-B
(0.75 g mmolꢀ1 of substrate)), none of the activated ester 3 was
observed with the four esters (13–16) and activating agents (7–
10, Fig. 1) studied. In all cases it appeared as though reaction
reversibility was problematic and that if the activated ester 3
had formed, it was rapidly attacked by the liberated methanol
(2), to give the starting ester again. Despite solvent-swapping to
toluene, in order to increase the reaction temperature, and
attempting to distil off the methanol as it formed, all attempts
to force the formation of the activated ester failed. This is in
Benzoate esters
Having met failure with the alkanoate esters, attention was
turned to therapeutically important benzanilide derivatives,22–25
the challenges being to secure a successful enzyme-catalysed
synthesis of an activated ester, and to observe that successfully
react with anilines under the same reaction conditions, before
attempting the one-pot, two-step process.
Due to the problems associated with reaction reversibility in
the methyl alkanoate cases, both methyl and butyl benzoate
esters were employed here, in the expectation that the larger
butyl alcohol would be less likely to attack the activated ester as
it forms, and thus reversibility would be minimised. Unfortu-
nately, with both esters (17, R ¼ Me or Bu and R1 ¼ H), under
the standard enzyme-catalysed conditions above, no activated
ester was observed with acetone oxime (7) or the halogenated
alcohols (8–10). Furthermore, optimisation of the enzymatic
step was not attempted, since, in a separate study, it was shown
that the activated ester 3 (R ¼ Ph, OACT ¼ 7, prepared chemi-
cally) did not react at all with all anilines studied. Presumably,
the conjugated benzene ring renders the activated ester too
unreactive to react with weak aniline nucleophiles. Interestingly
however, this activated ester did react with benzylamine (46%
isolated yield of the corresponding amide). However, despite
this success, this result was not followed up since, in a separate
reaction, a positive background result was observed between the
standard ester, butylbenzoate 17 (R ¼ Bu, R1 ¼ H), and ben-
zylamine when catalysed by CAL-B alone (i.e. without acetone
oxime), thus invalidating the need to develop a new catalytic
process to these targets.
Fig. 1 Activating agents and starting esters screened and the corre-
sponding target amides. References for the use of these activating
agents: 7,12–16 8,12 9,12 10,17,18 11.19,20
1610 | RSC Adv., 2014, 4, 1609–1615
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Table 1 Products of the CAL-B catalysed reaction between butyl esters 17 (R = Bu) and ethylene glycol (11)a
Entry
Ester
Product
Compound
Yieldb (%)
Selectivity (%) (monomer: dimer)c
1
22
34
100
2
3
4
23
24
25
33
29
19
100
100
100
5
6
26
27
32
100
n.r.
n.d.
Contrastingly, when ethylene glycol (11) was used as the there is no evidence of dimer formation and the reaction is
activating agent,20 up to 33% isolated yield of glycol ester 22 was 100% selective for the mono-ester product.
obtained from methyl benzoate, and 38% of 22 from butyl
Additionally, increasing the amount of CAL-B to (1.5 g) gave
benzoate, both with 100% selectivity for the formation of the the desired ester in up to 81% isolated yield with methyl-
mono-ester, upon reaction with CAL-B under the usual condi- benzoate, still with complete selectivity for the mono-ester; a
tions, Table 1. This process appeared to be generic, and a range promising result, especially as the only current methods to such
of six butylbenzoates (17, R ¼ Bu; Fig. 1) were cleanly converted compounds are non-sustainable processes,26,27 and since the
to the corresponding glycol mono-esters (22–26), with no dimer yield of the rst step is immaterial here anyway, so long as
formation observed at all, Table 1.
enough activated species is present in the reaction to turn over
Table 1 shows that, whilst the isolated yields of the products the catalytic cycle at a reasonable rate. As such, with a successful
may only be modest (19–34%) under these reaction conditions, enzyme-catalysed synthesis of these activated esters at hand,
yield is only really effected by a strongly electron-donating attention turned to their reactions with anilines, in the hope that
amino group (entry 6), but in all cases where product is seen, the terminal hydroxyl group would wrap around and H-bond to
the ester carbonyl thus activating it to attack by nucleophiles, as
has been demonstrated in related systems, Fig. 2.20
Unfortunately, despite such precedent, all reactions with a
variety of primary and secondary aliphatic amines and aniline
failed to produce any desired amide products, even when
attempts were made to optimise the reaction conditions by
using non-chelating solvents, and incorporating additional
chelating Lewis acids.
Again it was assumed that the lack of reactivity here was, in-
part, due to the benzene ring being in conjugation with the ester
Fig. 2 Proposed activation method of the ethylene glycol monoesters
prepared herein.20
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Table 2 Preliminary investigation of the reaction between 3 (R ¼ Bn,
OACT ¼ 7) and various nucleophilesa
nucleophiles are known to react with the corresponding acid
chloride (Table 2), suggesting that the activated ester prepared
here could be a stable, complementary acylating agent to more
traditional, yet toxic, corrosive and unselective acid chlorides
in its own right, as well as being a potential reaction partner in
the catalytic cycle proposed here.
Electrophile
Activated ester
3 (R ¼ Bn, OACT ¼ 7,
% yield)b
2-Phenylacetyl
chloride
(% yield)
Entry
Nucleophile
Based on the selectivity observed between the two anilines in
Table 2 (entries 1 and 2 – which was further conrmed by a
competition reaction between the two amines – see ESI†)
further study of the chemoselectivity of this reaction was carried
out, especially since it is recognised that amides, such as 28,
possess important biological activity; for example, derivatives
are known to behave as: novel haemoglobin oxygen-affinity
decreasing agents;36 non-natural modulators of quorum
sensing in Pseudomonas aeruginosa;37 biphenylacetamide-
derived inhibitors of BACE1;38 and an intermediate in the
synthesis of a RAD51 inhibitor that disrupts homologous
recombination.39
1
2
3
4
5
6
7
PhNH2
81
95 (ref. 29)
91 (ref. 30)
89 (ref. 31)
98 (ref. 32)
100 (ref. 33)
93 (ref. 34)
74 (ref. 35)
PhNHMe
PhCH2NH2
PhCH2NHMe
PhCH2OH
PhOH
n.r.
100
13
n.r.
n.r.
n.r.
PhSH
a
Reagents and conditions: 3 (R ¼ Bn, OACT ¼ 7) (1 eq.), nucleophile
b
(1 eq.), MTBE (1 M), 55 ꢁC for 8 hours. Isolated yields. n.r. ¼ no
reaction.
Table 3 details the products obtained in the study of this
and the delocalisation of aniline's nitrogen lone pair hampering chemoselective reaction between ester 3 (R ¼ Bn, OACT ¼ 7)
reactivity. Thus, since the only complete success observed so far and various aniline derivatives.
had been with the alkyl ester—vinyl acetate—attention was
For each aniline studied, the reaction was also carried out
turned to a different alkyl ester, butyl-2-phenylacetate (18, with the analogous N-methyl aniline, but in all cases, no reac-
Fig. 1), a compound in which the benzene ring has been tion occurred whatsoever. Electron-rich primary anilines
extended out of conjugation with the ester by one methylene (entries 2 and 5) reacted extremely cleanly, giving 100% yields of
unit, and thus should be more reactive.
the expected amides with both anilines. Results which suggest
Based on the wealth of knowledge that exists for optimising that the increased nucleophilicity of the anilines aids their
lipase-catalysed reactions in organic solvents,28 it was envis- reaction with the activated ester, but that such reactivity cannot
aged that a successful catalytic process (Scheme 1) could be overcome the increased sterics associated with the N-methyl-
further developed more easily if reactivity was secured in ated compounds. In contrast, the electron rich hydroxylated
chemical steps [3–5], aer which, efforts could be focussed on compounds (entries 3 and 4) gave no reaction products with
optimising the rst enzyme-catalysed steps [1] and [2], either the primary or secondary anilines—presumably the result
knowing that reaction with the activated species was assured. of H-bonding inuencing reactivity rather than electronic
With this in mind, further development of the process began factors alone increasing nucleophilicity. Furthermore, a range
by preparing the activated ester 3 (R ¼ Bn, OACT ¼ 7) chem- of yields occur with the halogenated primary anilines (entries 6,
ically (employing acetone oxime as the activating partner, 7 and 8; 92%, 40% and 83% respectively), ostensibly the result
since it had been previously shown to be a successful reaction of a subtle balance between mesomeric and inductive effects.
partner with vinyl acetate), and analysing its reactivity with Interestingly, the rather more drug-like compound (entry 9)
various anilines, before moving on to study its formation pleasingly gave the desired acylated product in 92% isolated
enzymatically.
yield; its X-ray crystal structure can be seen in Fig. 3;40 in recent
Interestingly, in the event, it was found that the activated times, it has been shown that N-phenyl-p-phenylenediamine
ester displayed similar chemoselectivity to that observed in the (entry 9) is an important intermediate used in the synthesis of
vinyl acetate work,11 in that there was selectivity for N-nucleo- anti-depressants,41 tyrosine kinase inhibitors,42 antivirulents43
philes over O- and S-based ones, and that primary anilines were and platelet-derived factor (PDGF) receptor phosphorylation
completely selective over secondary anilines. For example, inhibitors.44 Additionally, it has also been used in the synthesis
Table 2 shows that aniline (entry 1) reacted well with the of biodegradable hydrogels,45 thus, such selective acylation at
activated ester, whereas, N-methylaniline (entry 2) did not the primary nitrogen, as seen here, could be exploited in further
react at all. Moreover, whilst the difference in reactivity derivatisation of the molecule, which in turn, could be useful in
between the homologous compounds benzylamine (entry 3) further enhancing its utility.
and N-methylbenzylamine (entry 4) is not as stark, the N-
Similarly, the drug-like pyrrolidyl derivative (entry 10), was
methylated analogue does possesses severely reduced reac- also acetylated in 50% yield, related compounds of which have
tivity compared to the primary amine. Furthermore, other been used in the synthesis of many pharmaceutical composi-
nucleophiles, such as benzyl alcohol (entry 5), phenol (entry 6) tions, the preparation of novel epidermal growth factor receptor
and thiophenol (entry 7) did not react with the activated ester, (EGFR), and c-Jun N-terminal kinases (JNK) inhibitors respec-
indicating that not only is the ester selective for primary tively, which are all currently in patent. Similarly, such
anilines over N-methylanilines, but that it also may be selec- compounds have also been used in the preparation of
tive for amines per se, as seen before.11 Importantly, all antibacterials.46
1612 | RSC Adv., 2014, 4, 1609–1615
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Table 3 The reaction between 3 (R ¼ Bn, OACT ¼ 7) and various substituted anilinesa
Entry
Amine
Product
Compound
Yieldb (%)
1
28
81
2
3
29
30
100
n.r.
4
5
6
31
32
33
n.r.
100
92
7
8
34
35
40
83
9
36
92
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Table 3 (Contd.)
Entry
Amine
Product
Compound
Yieldb (%)
10
37
50c
a
Reagents and conditions: 3 (R ¼ Bn, OACT ¼ 7) (1 eq.), amine (1 eq.), MTBE (1 M), 55 ꢁC for 8 hours. b Isolated yields. c Calculated from the 1H NMR
of the crude reaction mixture. n.r. ¼ no reaction.
improvements are to be made if it is to be synthetically, and
industrially relevant. The most probable chances of success are
likely to come through a screen to determine which activated
agents react best with the amines of interest, followed by
exhaustive enzyme screening or directed evolution of enzymes,
in order to nd suitable enzymes that are capable of forming the
activated ester.
Fig. 3 X-ray crystal structure of 36.40
Acknowledgements
The authors would like to thank the Overseas Research Students
Unfortunately, despite the chemoselective successes
Awards Scheme (ORSAS) for funding (SL) and the EPSRC X-ray
between the reactions of the activated ester with anilines, all
Crystallography Service.47
attempts to prepare it using CAL-B failed, despite attempted
optimisation of solvent (DCM, PhMe, MTBE), reaction temper-
atures (room temperature up to 90 ꢁC), the incorporation of
additives, the attempted distillation of methanol as it formed
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