Catalytic amidation of unactivated ester derivatives mediated by trifluoroethanol

Article abstract of DOI:10.1039/c5cc02895g

A catalytic amidation method has been developed, employing 2,2,2-trifluoroethanol to facilitate condensation of unactivated esters and amines, enabling the synthesis of a range of amide products in good to excellent yields. Mechanistic studies indicate the reaction proceeds through a trifluoroethanol-derived active ester intermediate.

Full text of DOI:10.1039/c5cc02895g

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Catalytic Amidation of Unactivated Ester Derivatives
Mediated by Trifluoroethanol
Cite this: DOI: 10.1039/x0xx00000x
Nicola Caldwell,a Craig Jamieson,*,a Iain Simpsonb and Allan J. B. Watsona
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Within our own laboratories, we have recently focused our attention
on the development of catalytic methods for the amidation of simple
ester starting materials, with a view to addressing some of the
outstanding issues associated with this reaction. We have previously
described two mild, efficient processes involving base-catalysed
amidation of esters using amino alcohols (Scheme 1).21,22 Both of
these protocols have been applied to an extensive range of
A catalytic amidation method has been developed, employing
2,2,2-trifluoroethanol to facilitate condensation of unactivated
esters and amines, enabling the synthesis of a range of amide
products in good to excellent yields. Mechanistic studies
indicate the reaction proceeds through a trifluoroethanol-
derived active ester intermediate.
Amide bonds are ubiquitous in both natural and synthetic substrates, generating amido-alcohol products exemplified by 1 in
molecules.1 This important functionality constitutes the fundamental excellent yields. Mechanistic studies have indicated the progression
repeat unit in proteins, which are essential for sustaining biological of the reaction through an ester intermediate (2), followed by
processes. Amide bonds also commonly feature in small molecules, rearrangement to the thermodynamically more stable amide.23
particularly within a pharmaceutical context. Approximately a However, the presence of an alcohol moiety in the starting material
quarter of registered drug molecules contain an amide bond2 and, in order to facilitate this initial transesterification event was a pre-
consequently, amidation is the most commonly executed requisite to enable application of this methodology. In order to
transformation in medicinal chemistry laboratories.3,4 However, further develop and extend this catalytic process, we were eager to
popular methods for the preparation of amides from carboxylic acids establish whether exogenous alcohol-derived additives could be
utilising coupling agents suffer from inherent drawbacks.5 The most employed in this process to form an active ester in situ, thus enabling
significant of these disadvantages from a sustainability perspective is the direct reaction of simple ester derivatives with amines. Herein,
the requirement for stoichiometric quantities of coupling reagent, we report our efforts towards the development and exemplification
and the resulting generation of equimolar by-products. Based on this, of this catalytic amide bond forming process.
several catalytic amidation methods have recently emerged which
seek to improve the atom economy of this process, thus minimising
environmental impact.6-12
In relation to the direct conversion of esters to amides, a number of
stoichiometric approaches have been developed13,14 to overcome the
protracted reaction times and high temperatures associated with
aminolysis. More latterly, catalytic approaches to aminolysis of ester
derivatives have been reported.15-20 Despite the obvious utility of
these catalytic methods which enable amidation of unactivated ester
moieties, there still remain a number of limitations with regard to
their practical application. In particular, some of the approaches
reported are of limited substrate scope with respect to the acylating
species, or rely on the use of rare earth metals which presents a
concern from a sustainability perspective.
Scheme 1. Base-catalysed amidation of esters.
To assess the feasibility of applying external additives in this
methodology, several common peptide-coupling additives were
examined in a model reaction examining the conversion of 3 to 5
(Scheme 2). These additives (HOAt,24 HOBt,25 HOCt26, Oxyma,27
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N-hydroxysuccinamide,
2,2,2-trifluoroethanol,
and From consideration of the raw data,28 and inspection of the half-
hexafluoroisopropanol) were subjected to conditions previously normal plot associated with the design (Figure 1(a)), it was inferred
optimised for our progenitor process.21 Results of this study that perhaps unsurprisingly, temperature was the most significant
indicated that only 2,2,2-trifluoroethanol (TFE) gave any measurable factor in influencing conversion, with elevated temperatures proving
conversion (6%) to amide product 5 when used in stoichiometric optimal. What was less obvious from the raw data28 was the
quantities. No significant conversion was observed for any of the interaction between base and catalyst loading, which appeared to
other additives screened, possibly due to the reduced nucleophilicity have a significant effect on the conversion (Figure 1(b and c)). An
of these systems, and hence poor reactivity in the initial optimum balance appeared to exist between equivalents of TFE and
transesterification step.
K3PO4, with conversion rapidly diminishing when catalytic
quantities of each were employed. This effect was particularly
exacerbated at lower temperatures (Figure 1b) and could be
attenuated by performing the reaction at 90 ˚C. Based on all of the
above, it is apparent that using a DoE-based optimisation strategy
provides greater levels of process understanding than could be
obtained using traditional optimisation approaches, particularly in
relation to identifying the interaction between two variables.
Scheme 1. Screening of additives for direct amidation
Based on this initial survey, TFE was prioritised for further
investigation to establish if modifying reaction conditions could
improve conversion. To this end, alternative bases (BEMP, DBU,
K3PO4, NaH, and t-BuOK) and solvents (acetonitrile, DMF, NMP,
THF, and toluene) were investigated for use in the model reaction.
The most effective combinations are summarised in Table 1.28 From
consideration of this data, both THF and toluene appeared to be
effective solvents for this process. Increased conversions to product
were observed when using either K3PO4 or NaH as the base,
however some hydrolysis of the ester starting material was observed
in cases where NaH was employed. Importantly, control reactions
with no base or TFE additive consistently gave no conversion as
determined by HPLC. As a result of this, and due to the relative ease
of handling of K3PO4, the combination of K3PO4 in THF was
progressed for subsequent optimisation of reaction conditions.
base
K3PO4
NaH
solvent
THF
Conversion (%)
Figure 1. (a) Half-normal plot indicating effect of temperature (A)
on conversion; (b) response surface showing effects of TFE and
K3PO4 equivalents on conversion of 3 to 5, modeled at 60 °C and (c)
response surface showing effects of TFE and K3PO4 equivalents on
conversion of 3 to 5, modeled at 90 °C.
14
19
13
14
THF
K3PO4
NaH
PhMe
THF
As enabling a catalytic transformation was the primary focus of our
design process, we were keen to investigate whether lower catalyst
loadings of TFE could be tolerated. Based on analysis of the
response surface, we reasoned that using a full equivalent of the
relatively inexpensive base could offset the resulting drop in
conversion, particularly when the reaction was carried out at higher
temperatures (Figure 1(c)). Pleasingly, employing one equivalent of
K3PO4 allowed the reaction to proceed using only 20 mol% TFE.
These optimised conditions (20 mol% TFE, 1 equiv K3PO4, 90 °C,
22 h) resulted in an isolated yield of 86% for target compound 5
(Scheme 2), representing a significant improvement to the initial
conversion of 6% obtained in the screening phase of the study.
Table 1. Screening of alternative bases and solvents. aDetermined by
HPLC with reference to an internal standard.28
In order to expediently optimise reaction conditions using the
conversion of ester 3 to amide 5 as a model process, the powerful
statistical approach of Design of Experiments (DoE) was utilised to
simultaneously examine the effects of multiple factors in an efficient
manner.29 A two-level, half-fractional central composite design was
selected using Design ExpertTM software.30 We envisaged that
application of a central composite design in this optimisation
campaign would give a more accurate representation of any
curvature in the resulting response surface. In this study, we elected
to explore the following variables: reaction time (8 – 22 h),
temperature (40 – 80 °C), concentration (0.5 – 2 M), catalyst loading
(0.2 – 1 equivalents), and base loading (0.2 – 1 equivalents).28
Again, it should be emphasised that carrying out the corresponding
control reactions in the absence of either TFE or K3PO4 resulted in
less than 2% conversion being observed by HPLC (Scheme 2),
confirming that the reaction does not proceed via direct aminolysis,
and is likely to be facilitated through the formation of a TFE-derived
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ester intermediate. It is interesting to note that the reaction does not amide 5 from the methyl ester starting material 3 showed trace
proceed in the absence of a potassium derived base, suggesting that amounts (4%) of intermediate 27 throughout the progression of the
any ammonium salt that could result from combination of the amine reaction.
substrate and TFE is not reactive enough to attack the starting ester,
suggesting an important role in the overall reaction mechanism.
Scheme 2. Optimised conditions in comparison to control reactions.
Having identified optimum reaction conditions using a DoE-based
approach, we subsequently sought to investigate the general utility of
this methodology. Accordingly, a range of ester and amine starting
materials were assessed for their applicability in this reaction
manifold (Scheme 2). A broad range of amides could be prepared
using the conditions developed in the current study. Several aryl
esters were successfully coupled with benzylamine, furnishing good
to excellent yields of the corresponding amide products (5–9). The
reaction was found to be tolerant of both electron-withdrawing (6–7)
and electron-donating (9) functionalities, with the latter exhibiting a
slight decrease in yield.
Aliphatic esters were also tolerated as evidenced by examples 10–14,
including the use of two amino-acid derived building blocks, (13–
14). Unfortunately, significant erosion of enantiopurity was observed
when using an α-chiral ester starting material to afford compound 14
(ee = 8% as determined by chiral HPLC), representing a potential
limitation of this methodology. Efforts are currently ongoing to
identify conditions which address this issue.
Esters containing a heterocyclic motif (15–18) were competent
substrates; pyridine (15), pyrimidine (16), pyrazine (17), and
thiophene-derived (18) esters all gave excellent yields of the
corresponding amides. Varying the amine coupling partner
facilitated access to a raft of additional amide products. Aliphatic
amines such as cyclohexanemethylamine could be successfully
employed to form amides with heterocyclic (19) and aliphatic (20)
esters. Piperidine (21) and substituted derivatives of piperidine (22)
and piperazine (23) represented several examples of effective
coupling using a secondary amine. Extending the chain length of the
amine starting material to form homologated products such as 24 and
25 was also tolerated. Finally, we were keen to apply our
methodology to the synthesis of a medicinally relevant compound.
Accordingly, the experimental Ampakine Farampator (26), which is
in phase II clinical trials for ADHD,31 could successfully be prepared
in one step using our newly developed process.
In the concluding part of our study, additional mechanistic
investigations were carried out. As we reasoned that the reaction
a
Scheme 2. Assessment of substrate scope. Isolated yields shown.
isolated in 8% ee as determined by chiral HPLC;28 bSynthesised
proceeded via a trifluoroethyl ester intermediate, represented by 27,
this moiety was independently synthesised32 and subjected to
from the corresponding ethyl ester starting material.
standard reaction conditions (Figure 2). The conversion of ester
derivative, 27, to amide product, 5, was monitored by HPLC over a
22 hour time period. Results from this analysis indicated
consumption of the trifluoroethyl ester derivative, with concomitant
formation of the desired product. Amide 5 was isolated in 77% yield
from this process, which is in broad agreement with previous yield
obtained for this substrate. These observations validated our
proposal that an active ester derivative was the corresponding
acylating species under the optimised reaction conditions. In
addition to this, subsequent LCMS analysis of the formation of
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