B(OCH2CF3)3-mediated direct amidation of pharmaceutically relevant building blocks in cyclopentyl methyl ether

Article abstract of DOI:10.1039/c5ob01801c

The use of B(OCH₂CF₃)₃ for mediating direct amidation reactions of a wide range of pharmaceutically relevant carboxylic acids and amines is described, including numerous heterocycle-containing examples. An initial screen of solvents for the direct amidation reaction suggested that cyclopentyl methyl ether, a solvent with a very good safety profile suitable for use over a wide temperature range, was an excellent replacement for the previously used solvent acetonitrile. Under these conditions amides could be prepared from 18 of the 21 carboxylic acids and 18 of the 21 amines examined. Further optimisation of one of the low yielding amidation reactions (36% yield) via a design of experiments approach enabled an 84% yield of the amide to be obtained.

Full text of DOI:10.1039/c5ob01801c

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B(OCH2CF3)3-mediated direct amidation of
pharmaceutically relevant building blocks
Cite this: DOI: 10.1039/c5ob01801c
in cyclopentyl methyl ether†
Valerija Karaluka,a Rachel M. Lanigan,a Paul M. Murray,b Matthew Badlandc and
Tom D. Sheppard*a
The use of B(OCH2CF3)3 for mediating direct amidation reactions of a wide range of pharmaceutically
relevant carboxylic acids and amines is described, including numerous heterocycle-containing examples.
An initial screen of solvents for the direct amidation reaction suggested that cyclopentyl methyl ether, a
solvent with a very good safety profile suitable for use over a wide temperature range, was an excellent
replacement for the previously used solvent acetonitrile. Under these conditions amides could be pre-
pared from 18 of the 21 carboxylic acids and 18 of the 21 amines examined. Further optimisation of one
of the low yielding amidation reactions (36% yield) via a design of experiments approach enabled an 84%
yield of the amide to be obtained.
Received 28th August 2015,
Accepted 8th September 2015
DOI: 10.1039/c5ob01801c
www.rsc.org/obc
methods are largely limited to more reactive carboxylic acids
and amines (e.g. simple relatively lipophilic alkyl or aryl
Introduction
Amides are highly important in pharmaceuticals and it is well systems), with very few successful reactions of functionalised
documented that amidation is one of the most commonly compounds being reported. The synthesis of pharmaceutically
used processes in the synthesis of medicinally relevant com- relevant compounds inherently requires the amidation of such
pounds.1 Amides are typically synthesised either via prepa- polar functionalised molecules,8 however, with heterocyclic
ration of a highly reactive acyl derivative (acyl chloride, mixed compounds in particular being an essential component
anhydride, etc.) or via use of a coupling reagent.2 These pro- of many drug molecules. These highly polar heterocycle-
cesses are not without significant drawbacks, however, as they containing acids and amines often show low reactivity in
often involve the use of toxic reagents or solvents and lead to direct amidation reactions (e.g. electron-deficient amino-
the generation of large quantities of waste products. As a con- heterocycles are typically very poor nucleophiles), and the pres-
sequence of this, there has been considerable interest in the ence of co-ordinating heteroatoms is incompatible with many
development of alternative methods for achieving direct ami- of the catalytic amidation systems reported to date. In our pre-
dation between carboxylic acids and amines, a process which vious work, we have shown that borate esters9 such as B(OMe)3
formally only requires the removal of a molecule of water.3 and B(OCH2CF3)3 are effective amidation reagents,10,11 and
Notable developments have included the identification of that purification of the amide products can be achieved using
numerous catalysts for mediating amidation reactions under a simple filtration work-up in many cases, without any need
dehydrating conditions (e.g. Dean–Stark water removal or for chromatography or aqueous work-up.11 In this paper we
molecular sieves) including systems based around boron,4 report new conditions for direct amidation using a simple
group IV metals,5 or other inorganic compounds.6 Progress borate ester that are effective with a wide range of pharma-
has also been made on the improvement of direct thermal ceutically relevant carboxylic acids and amines.
amidation reactions without
a
catalyst.7 However, these
aDepartment of Chemistry, University College London, 20 Gordon St, London,
WC1H 0AJ, UK. E-mail: tom.sheppard@ucl.ac.uk; Tel: +44(0) 20 7679 2467
bPaul Murray Catalysis Consulting Ltd, 67 Hudson Close, Yate, BS37 4NP, UK
cPfizer Global Pharmaceutical Sciences, Discovery Park, Ramsgate Road, Sandwich,
Results and discussion
Solvent screen
In our original report of borate-mediated amidation reactions
we screened a selection of different solvents for the B(OMe)3-
mediated reaction between phenylacetic acid 1a and benzyl-
amine 2 to give amide 3a.10 From this initial screen, aceto-
Kent, CT13 9NJ, UK
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectroscopic data, ‘Design of Experiments’ reaction optimisation data,
and 1H and 13C NMR spectra. See DOI: 10.1039/c5ob01801c
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nitrile was selected as a solvent for further study and this was other solvents examined. Other ether solvents including THF,
employed for subsequent amidation reactions with other 2-MeTHF and TBME gave the amide in moderate yield, as
borate esters from which B(OCH2CF3)3 emerged as the most did ethyl acetate. The latter example elegantly demonstrates
promising reagent, especially for less reactive substrates. the compatibility of esters with the reaction conditions.
However, no subsequent screen of solvents using B(OCH2CF3)3 We selected CPME for further use as it has a relatively high
was carried out. In general, amidation reactions with less reac- boiling point (bp 106 °C), providing scope for increasing the
tive substrates were observed to proceed more effectively at reaction temperature when studying the amidation of less-reac-
higher temperatures, but using acetonitrile as solvent, this led tive substrates. Preliminary studies suggested that whilst many
to the need to carry out reactions of particularly difficult sub- heterocyclic acids/amines may not readily dissolve in CPME at
strates at 100 °C in a sealed tube. Even under these conditions, room temperature, they typically dissolve and react at higher
very unreactive substrates such as the poorly nucleophilic temperatures.
2-aminopyridine gave <20% yield of the corresponding
Application to pharmaceutically relevant carboxylic acids and
amines
amide.11 Before challenging our amidation method with a
set of highly functionalised acids and amines, we therefore
elected to carry out a further solvent screen to determine In order to challenge the scope of the B(OCH2CF3)3-mediated
whether other solvents might be more suitable for carrying out direct amidation reactions we studied the reaction of sets of 21
B(OCH2CF3)3-mediated amidation reactions (Scheme 1 and carboxylic acid and 21 amines specifically selected by research-
Table 1).12 As in our previous work, we used the reaction of ers in the pharmaceutical industry as ‘difficult substrates’
phenylacetic acid and benzylamine as a benchmark to screen which can often prove incompatible with newly developed syn-
the different solvents. The amidation product in this case can thetic methodology.14 Standard reaction conditions (2 eq.
easily be isolated rapidly via a filtration work-up, without the B(OCH2CF3)3, CPME, 100 °C, 5 h) were examined with all of
need for aqueous work-up or chromatography.
the compounds in the first instance, with the temperature or
Dimethylsulfoxide (entry 2), selected as it readily dissolves the reaction time being increased if required for less reactive
most polar acids/amines, was a poor solvent for the reaction. examples.
Ethereal solvents (entries 3–8) proved particularly promising,
however, although it should be noted that there was consider-
Screen of functionalised carboxylic acids
able variation in yield within this class of solvent. tert-Amyl In order to provide a good comparison of the reactivity, the
methyl ether (TAME, entry 3) and cyclopentyl methyl ether acids were all examined in direct amidation reactions with
(CPME, entry 4)13 were both excellent solvents for the amid- benzylamine as the nucleophile (Scheme 2). Pleasingly the
ation reaction, whereas the use of 4-methyltetrahydropyran standard procedure worked well for the vast majority of car-
(entry 5) resulted in only a moderate yield of the product. boxylic acids tested (18/21). Unless otherwise indicated, the
Notably, in this latter solvent immediate precipitation was amide product could be isolated via a simple solid phase fil-
observed on mixing the acid/amine suggesting that salt for- tration procedure without the need for aqueous work-up or
mation is particularly favourable. This was not the case in the chromatography. Substrates containing free alcohols readily
gave the corresponding amides in good yield (3b, 3c, 3l). 3-
Fluorophenylacetic acid 1d was notably less reactive than the
parent compound 1a, giving only 69% of amide 3d. Pleasingly,
a wide range of heterocyclic carboxylic acids underwent amida-
tion in excellent yield, including acids containing a pyridine
(3e), a pyrazine (3f), a 7-azaindole (3h), an indazole (3i) and a
Scheme 1 Direct amidation between phenylacetic acid and
benzylamine.
pyrazole (3j), although with the less reactive examples the reac-
tion temperature had to be increased to 125 °C. The 2-pyri-
done/2-hydroxypyridine substrate 1g gave only a moderate
yield of the amide 3g even at this higher reaction temperature,
however. With some of the amides containing basic nitrogen
heterocycles, purification via the standard solid-phase work-up
was not possible due to absorption of the product on the
Amberlyst 15 resin. However, in some cases replacement of
this strongly acidic resin with Amberlite IRA86 carboxylic acid
resin enabled the products to be isolated without chromato-
graphy (3e–3f). In other cases, purification by chromatography
was necessary (3g–3j). Functionalised aliphatic carboxylic
acids also underwent amidation efficiently including sub-
strates containing acetamides (3k, 3l), free hydroxyl groups
(3c, 3l, 3m) and a lactam (3n). The amino-acid derivatives N-
acetylhydroxyproline (3m), L-pyroglutamic acid (3n), Boc-pipe-
Table 1 Direct amidation between 1a and 2 in a variety of solvents
Entry
Solvent
Temperature
Yielda
1
2
3
4
5
6
7
8
9
MeCN
DMSO
80
80
80
80
80
80
80
80
80
87%
35%
88%
87%
43%
58%
56%
53%
50%
tert-Amyl methyl ether (TAME)
Cyclopentyl methyl ether (CPME)
4-Methyltetrahydropyran
Tetrahydrofuran (THF)
2-Methyltetrahydrofuran (2-MeTHF)
tert-Butyl methyl ether (TBME)
Ethyl acetate (EtOAc)
a Isolated yields.
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Scheme 2 Direct amidation reactions of functionalised carboxylic
acids; aPurified by column chromatography; bAmberlite IRA86 (CO2H)
resin used instead of Amberlyst 15; cAmberlyst 15 resin was not used;
d24 h, 125 °C; e24 h; fDetermined using an organic chiral shift reagent;15
gDetermined by derivatisation with Marfey’s reagent;16 hDetermined by
HPLC using a chiral stationary phase;17 iPurified by recrystallisation; no
solid-phase work-up.
Scheme 3 Direct amidation reactions of functionalised amines;
aPurified by column chromatography; b125 °C, 24 h; cAmine hydrochlo-
ride salt was used; Et3N was added to the reaction; dDetermined by
HPLC using a chiral stationary phase;17 e24 h.
the carboxylic acids above, we chose to study their reaction
with a standard reaction partner (phenylacetic acid 1a) in
order to provide a good understanding of their comparative
reactivity. Heterocyclic amines are notoriously unreactive sub-
strates for amidation reactions as the strongly electron-with-
drawing nature of many nitrogen heterocycles makes the
adjacent amine an extremely poor nucleophile. Low yields of
amide were obtained from 2-aminopyridine (5a) and 2-amino-
pyrimidine (5b), but the corresponding 2-aminopyrazine
underwent amidation effectively (5c). An electron-deficient
aniline bearing a cyano group also gave a reasonable yield of
the corresponding amide 5d. Pleasingly, amines containing a
benzimidazole (5e), a pyrazole (5f–5g) and an oxazole (5h) all
gave the amide derivatives in good yield. Relatively unreactive
aliphatic amines such as glycine methyl ester (5i), glycinamide
(5j), alaninamide (5k) and proline methyl ester (5l) were also
fairly good substrates, with some racemisation being observed
colic acid (3o) and Boc-phenylglycine (3p) were all good sub-
strates for the amidation with only the latter compound under-
going any significant degree of racemisation under the
reaction conditions. Mandelic acid (3q) gave only 24% yield of
the amide, however, and underwent almost complete racemi-
sation during the amidation process. The primary amide in
succinic acid monoamide 1r was compatible with the reaction
conditions, although the resulting amide 3r appeared to
undergo cyclisation to the corresponding N-benzylsuccinimide
during the solid-phase work-up procedure. As a consequence,
this compound was purified by recrystallisation to give the
amide 3r in 48% yield.
Screen of functionalised amines
We next went on to examine the amidation of a set of pharma-
ceutically relevant amines (Scheme 3). In a similar fashion to
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with the two chiral substrates. Moderate to good yields of borate-mediated amidation reaction is compatible with esters
amides were obtained from other challenging substrates (Table 1, entry 9), this suggests that reaction of this acetate
including a cyclic aminopyridine (5m), an amide-containing group is probably assisted by co-ordination of the adjacent
piperidine (5n), piperazin-2-one (5o) as well as a series of amide or carboxylic acid group to the boron atom. Cyclopropyl
piperazine derivatives (5p–5r). 2-Phenylpiperazine 4q reacted malonate derivative 1u gave a mixture of products 7a and 7b in
selectively at the least hindered amine to give amide 5q, with moderate overall yield. Thus, direct amidation of the carboxylic
no diamidated product being isolated from the reaction. acid competes with transamidation of the primary amide as
Amines which were supplied as hydrochloride salts could also well as ring opening of the highly activated cyclopropane.
be used directly in the amidation reaction, with triethylamine Heating cyclopropane 7a on its own or in the presence of
being added to liberate the free amine from the salt (5e, 5i– B(OCH2CF3)3 with/without benzylamine did not result in the
5k). In a similar manner to the reactions of the carboxylic formation of 7b, suggesting that these products were formed
acids described above, amide products containing basic nitro- via divergent competing reaction pathways in the original
gen atoms could not be purified via the solid-phase work-up amidation reaction.
procedure.
Design of Experiments optimisation of the reaction of
Unsuccessful amidation reactions
2-aminopyridine with phenylacetic acid
Amide 3s, derived from 2-hydroxyisobutyric acid could not be
obtained from the amidation reaction, with a complex mixture
of products being formed (Scheme 4). Attempted formation of
amide 5s also gave a complex mixture of products due to
numerous side-reactions. The formation of amides 5t and 5u
was unsuccessful as the corresponding amines 4t–4u were
In order to further demonstrate the utility of this amidation
method, we sought to take one of the less efficient amidation
reactions and optimise the procedure to give good yields of the
amide product. We selected the reaction between 2-aminopyri-
dine 4a and phenylacetic acid 1a to give amide 5a as this reac-
tion gave only a moderate yield of product (Scheme 5 and
insoluble in the reaction mixture. Although acetoxyacetic acid
Table 2). Indeed, under our original conditions (MeCN,
1t did undergo amidation of the carboxylic acid group, this
was accompanied by amidation of the acetoxy group to give
amides 6a/6b in moderate overall yield. Given the fact that the
100 °C), only a 12% yield of the amide was obtained
(entry 1).11 As can be seen above, switching the solvent to
CPME and raising the temperature led to a significant
improvement, giving a 36% yield of the amide (entry 2). In an
initial investigation, we explored whether dropwise addition of
one or more reagents to the reaction could lead to improved
yields of the product. Dropwise addition of the borate reagent
to a mixture of acid/amine led to a small improvement in the
yield (entry 3, 39%), whilst dropwise addition of a mixture of
acid/borate to the amine gave a similar yield (entry 4, 40%).
Interestingly, a significant improvement in yield (entry 5, 60%)
was observed by addition of the borate reagent dropwise to a
mixture of acid, amine and triethylamine suggesting that
Scheme 5 Reaction of 2-aminopyridine 4a and phenylacetic acid 1a.
Table 2 Study of the effect of different experimental procedures on
the yield of amide 5a
Entry Conditions
Yielda
1
2
3
4
5
MeCN, 100 °C
CPME, 125 °C
12%
36%
(39%)
(40%)
CPME, 125 °C, dropwise addition of borate
CPME, 125 °C, dropwise addition of borate/acid
CPME, 125 °C, 1 eq. Et3N, dropwise addition of borate (60%)
a Isolated yields; NMR yields in parentheses.
Scheme 4 Unsuccessful amidation reactions.
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Table 3 Factors and ranges covered in the ‘Design of Experiments’
optimisation of the formation of amide 5aa
Variable
Low
High
(eq. amine 4a)-(eq. acid 1a)
eq. B(OCH2CF3)3
eq. Et3N
−2
+2
3
3
Scheme 6 Reaction of 2-aminopyridine 4a and phenylacetic acid 1a to
give amide 5a under optimised conditions.
0.5
0.1
Solvent volume in borate solution
Solvent volume in reaction vessel
Addition rate (syringe pump)
Temperature
0.5 mL
0.5 mL
0.254 mL h−1
80 °C
2 mL
2 mL
13 mL h−1
125 °C
Table 4 ‘Optimised’ methods for the formation of amide 5a
a For full details of the Design of Experiments study, see the ESI.
Entry
Conditions
Yielda
1
2
3
4
3 eq. Et3N
58%
84%
83%
74%
3 eq. 4a, 0.1 eq. Et3N
3 eq. 1a; 3 eq. Et3N
3 eq. Et3N, Bu2O, 140 °C
a Isolated yields; 1 eq. 4a and 1 eq. 1a used unless otherwise stated.
factors simultaneously in order to evaluate the important para-
meters in a reaction using a relatively small number of experi-
ments.18 For the DoE optimisation, seven different continuous
variables were chosen for the study, and two solvents were eval-
uated: CPME and propionitrile (EtCN), the latter being chosen
as a higher boiling point equivalent to MeCN. The parameters
were investigated via a Resolution IV design consisting of 16
experiments plus two centre points. The factors studied and
the ranges covered are shown in Table 3.
Fig. 1 Model fit for DoE.
The results were analysed using MODDE 10 software,19 and
a model was generated to fit the data using multiple linear
regression (MLR) which provided a good fit to the data (Fig. 1).
The important factors in the reaction are shown in the coeffi-
cient plot in Fig. 2. By far the most significant factor in the
reaction was temperature with the higher temperature giving,
on average, a ∼27% increase in the reaction yield. The addition
of more borate reagent was also beneficial to the outcome, as
was the use of CPME as solvent rather than EtCN. None of the
other factors were found to be significant across the ranges
explored and there were no significant interactions between
the factors. The factor (amine-acid) explored the use of an
excess (3 eq.) of either the amine or the acid relative to the
other component. The design suggested that there was no par-
ticular benefit in using either an excess of the amine or the
acid, though it should be noted that the highest yields in the
DoE study were obtained with either an excess of acid or
amine at high temperature and with high borate loading in
CPME. The centre points of the DoE which employed equi-
molar quantities of acid and amine gave considerably lower
yields. In further studies we observed that an excess of one
reagent or the other was important in order to obtain a good
isolated yield of the amide (vide infra, Table 4).
Fig. 2 Coefficient plot showing the most important factors in the ami-
dation reaction.
keeping the borate concentration low and the overall reaction
mixture basic is advantageous.
With this information in hand, we then went on to carry
out a ‘Design of Experiments’ optimisation of this reaction
using the conditions where a solution of borate was added
dropwise to a mixture of amine/acid/Et3N as our starting
point. ‘Design of Experiments’ is a statistical approach to reac-
tion optimisation which enables the variation of multiple
Following on from the DoE study, we then determined the
isolated yield of amide 5a obtained under various sets of ‘opti-
mised’ conditions (Scheme 6 and Table 4). With equimolar
equivalents of acid and amine, the best isolated yield obtained
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was 58% using three equivalents of triethylamine (entry 1).
However, with an excess of either the amine (entry 2) or the
acid and triethylamine (entry 3) >80% isolated yield of amide
5a was obtained. The ability to carry out the amidation reac-
tion of a poorly reactive substrate with either an excess of the
acid or the amine provides flexibility in cases where one of the
coupling partners is particularly valuable. Furthermore,
switching the solvent to dibutyl ether (Bu2O), which has
similar properties to CPME but a higher boiling point, enabled
a 74% isolated yield to be obtained using equimolar quantities
of amine 4a and acid 1a at 140 °C. This correlates well with the
prediction of the DoE model that reaction temperature is by
far the most important factor affecting the yield of amide
obtained.
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Conclusions
An improved procedure has been developed for direct amida-
tion reactions with B(OCH2CF3)3 using CPME as the solvent.
The method was successfully applied to a wide variety of phar-
maceutically relevant carboxylic acids and amines with only 6
of the 42 substrates failing to undergo the desired amidation
process. More than half of the amides could be isolated via a
simple filtration work-up without the need for chromato-
graphic purification. Furthermore, it was demonstrated that
optimisation of the amidation protocol for one of the lower
yielding substrates enabled the isolated yield of the amide to
be increased from 36% to 84%.
Acknowledgements
We would like to thank Pfizer and the Engineering and Physi-
cal Sciences Research Council (EPSRC) for providing a CASE
award to VK, and the University College London Department
of Chemistry for providing a studentship to RML. We would
also like to acknowledge GlaxoSmithKline for providing the
carboxylic acid and amine sets, the EPSRC national mass
spectrometry facility in Swansea for analytical services, and the
EPSRC Dial-a-Molecule Network for supporting the Design of
Experiments studies.
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