Practical preparation of challenging amides from non-nucleophilic amines and esters under flow conditions

Article abstract of DOI:10.1039/c4cc07129h

A fast and efficient protocol for the formation of amides from low nucleophilic amines and esters in flow is described. Products were obtained in good to excellent yields and with the advantage of simultaneous mixing of all reagents at once, avoiding steps for intermediate formation. The protocol is also suitable to be combined with ester synthesis, resulting in the preparation of amides in-line from haloarenes. This journal is

Full text of DOI:10.1039/c4cc07129h

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Practical preparation of challenging amides from
non-nucleophilic amines and esters under flow
conditions†
Cite this:DOI: 10.1039/c4cc07129h
Received 10th September 2014,
Accepted 9th October 2014
Johannes L. Vrijdag,a Francisca Delgado,b Nerea Alonso,bc
Wim M. De Borggraeve,*a Natalia Perez-Maciasb and Jesus Alcazar*b
´
´
DOI: 10.1039/c4cc07129h
www.rsc.org/chemcomm
A fast and efficient protocol for the formation of amides from low reactivity through pre-formation of metallic amides from
nucleophilic amines and esters in flow is described. Products were strong organometallic bases, such as alkyllithium and Grignard
obtained in good to excellent yields and with the advantage of reagents.4 This procedure is not suitable for molecules bearing
simultaneous mixing of all reagents at once, avoiding steps for sensitive functional groups that may also react in addition to
intermediate formation. The protocol is also suitable to be combined the amine. Second, the preparation of intermediate aluminium
with ester synthesis, resulting in the preparation of amides in-line from amides using organoaluminium reagents, such as trimethyl-
haloarenes.
aluminium.5 However, these reagents are highly pyrophoric,
hazardous and potentially thermally unstable. Third, the use of
The amide group is one of the most ubiquitous and important strong inorganic bases, such as potassium tert-butoxide.6 The
functionalities found in natural and synthetic organic compounds. procedure is more general, though it makes use of a high
It is omnipresent in high impact drug molecules (antibiotics, concentration of a strong base and, more importantly, it is
antiarrhythmic agents, sedatives, etc.), proteins, and related peptide quite sensitive to the amount of water and oxygen present in
drug products.1 Consequently, the American Chemical Society the reaction, which may compromise its use at larger scales.
Green Chemistry Institute Pharmaceutical Roundtable identified
Recently, we have reported a green procedure for amide
amide formation as a high priority research field, illustrating the formation in flow7 using Grignard reagents, i.e. the Bodroux
ongoing strong need for simpler, more convenient, inexpensive, reaction.8 This method has demonstrated its general applic-
and atom economical agents.2
ability and is suitable for primary and secondary, and aliphatic
The direct aminolysis of esters with amines is attractive due and aromatic amines. However, the use of tetrahydrofuran
to its simplicity, economy, and availability of starting materials. (THF) as the solvent results in a low solubility of most non-
Esters are stable, abundant in nature, usually easily accessible nucleophilic heterocyclic amines or precipitation of their
from a synthetic point of view, and hence equally available from corresponding magnesium amides. For instance, even though
commercial suppliers. Different conditions have been reported diluted solutions of 2-aminopyridine could be used, 4-amino-
for the direct amidation of esters.3 Nevertheless, there is a gap pyridine was unsuitable due to its poor solubility in THF.
when poor nucleophilic amines are used.
In our exploration of novel procedures for amide formation
To the best of our knowledge there are only 3 methods we decided to explore alternative bases for the Bodroux reaction.
described for the direct synthesis of amides from esters and Our aim is to increase the scope of this reaction especially
weak nucleophilic amines. First, the enhancement of their low focused on non-nucleophilic amines as these examples are
scarcely reported in the literature.4–6,8 Herein we present a novel
a University of Leuven, Department of Chemistry, Molecular Design and Synthesis,
Celestijnenlaan 200F, box 2404, BE3001 Heverlee, Belgium.
E-mail: wim.deborggraeve@chem.kuleuven.be; Fax: +32 16327990;
Tel: +32 16327693
b Department of Medicinal Chemistry, Janssen Research and Development,
Janssen-Cilag, S.A., C/Jarama 75, 45007 Toledo, Spain.
E-mail: jalcazar@its.jnj.com; Fax: +34 925245771; Tel: +34 925245750
c
´
´
Facultad de Ciencias y Tecnologıas Quımicas, Universidad de Castilla-La Mancha,
13071 Ciudad Real, Spain
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc07129h
Fig. 1 Experimental set-up of the flow system.
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procedure for the preparation of synthetically challenging product 3a in a comparable yield. This result is interesting
amides under continuous flow conditions mediated by lithium because the scope of reactivity for previous protocols was
bis(trimethylsilyl)amide (LHMDS). This base was selected due to limited to alkyl esters.4–6,8 Nitro compound 3b was obtained
its high basicity and low nucleophilicity which would improve in quantitative yield and easily purified as it precipitated
functional group tolerance compared to previously described spontaneously upon collection of the reaction mixture in a
organometallic reagents. Furthermore, the use of LHMDS allows 1 M solution of ammonium chloride. Electron-rich and
for mixing all reagents at the same time without preformation electron-deficient heterocyclic esters were also tolerated in the
of the metallic amide intermediate. Moreover, flow chemistry reaction (3c, 3d and 3e).
would not necessarily require using low temperatures as is the
case with batch protocols.9
Aliphatic esters also yielded the corresponding products 3f
and 3g. Notably, the Boc protecting group is permitted under
In an initial approach a solution containing the amine and these reaction conditions. However, ethyl phenylacetate proved
the ester, and a solution of the base were mixed in an LTF to be troublesome due to the competing deprotonation at the
(LTF-MX)10 chip using a dual syringe pump. The product was benzylic position which compromised the conversion of the
collected in an appropriate quenching solution (Fig. 1). 4-Amino- ester moiety into its corresponding amide 3h. The low nucleo-
pyridine was selected as a model of the amine reagent with low philicity of the base allows expanding the scope of this reaction
nucleophilic activity as it had presented difficulties in our to functional groups that would react with organolithium and
previous protocol.8 In order to get the amine in solution we Grignard reagents.4,8 This is demonstrated by the preparation
decided to use N,N-dimethylformamide (DMF) as the solvent.
of 3i where the cyano group remained unaltered, corroborating
The first attempt was performed using 1.1 equivalents of the selectivity of the protocol. Interestingly, in most afore-
both the amine and the base. The reagents were allowed to mentioned experiments the reaction products were obtained
react for 2 minutes at room temperature before the reaction pure after a simple extraction and trituration workup procedure,
was quenched. The moderate conversion observed was promising avoiding the need for chromatography.
because only the product and unreacted starting materials were
Second, the scope of the amines suitable for the reaction was
found in the crude mixture (Table 1, entry 1). The reaction then explored (Chart 2). The coupling of a selection of classical
approached completion upon simply doubling the amount of unreactive heterocyclic amines provided the desired products
base (entry 2): the reaction required a second equivalent of base 3j–n in acceptable to good yields. Both electron-deficient and
as the amide formed is more acidic than the amine, therefore electron-rich substrates were found to react surprisingly well.
preventing the amine to further react with the ester. Further 2-Aminobenzimidazole required the use of 3.3 equivalents of
attempts to reduce the reaction time by increasing the tempera- LHMDS to be fully deprotonated and selectively provided amide
ture or increasing the stoichiometric ratio of the amine did 3n. In this example the reaction outcome was slightly improved
not provide remarkable improvement in the reaction outcome at 50 1C. Low nucleophilic anilines were also suitable for this
(entries 3–9).
protocol and compounds 3o and 3p were obtained in 61% and
The substrate scope of both the ester and the amine reagent 78% yields. However, increasing the steric hindrance required
was then studied using the optimized conditions described higher temperatures and amide 3q was obtained in high yield
above (Table 1, entry 2). First, a series of esters was reacted with
4-aminopyridine (Chart 1). After successful conversion of ethyl
ester 1a to its corresponding amide 3a in 84% isolated yield, the
use of its corresponding trichlorophenyl ester gave the same
Table 1 Optimization of model reaction in flow
Entry
Eq. 2a
Eq. LHMDS
T/1C
tR/min
Conv.a
1
2
3
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.2
1.1
2.2
2.2
2.2
2.2
2.2
2.2
2.4
2.4
rt
rt
rt
rt
40
40
40
rt
2
2
1
0.5
2
1
0.25
2
36
98 (84)b
95
92
96
96
93
99
96
rt
1
a
b
Chart 1 Exploration of the ester scope.
Conversions determined as percentage by LC-MS. Isolated yield.
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is more useful when sensitive functionalities are required. In this
way compound 3t was prepared is good yield despite the
presence of the cyano group, normally a sensitive group when
alkyllithium and Grignard reagents are used. Other substituted
4 amino pyridines 3u–v and quinoline 3y also proceeded very
nicely in good yields. To complete the scope of 6-membered ring
heterocycles, pyridazine 3w and pyrimidine 3x were explored,
providing their corresponding amides in improved yields when
the reactor was heated at 50 1C.
Considering the promising results obtained for the conver-
sion of a 2,4,6-trichlorophenyl ester, a typical product of the
Manabe reaction,11 we decided to combine this amidation step
with our previously described flow carbonylation in a cascade
event.12 This combination would allow us to directly prepare
amides from low nucleophilic amines and the corresponding
aryl halides using an in-line procedure without the need of an
external CO source, i.e. a gas cylinder. This is very convenient as
the use of toxic carbon monoxide is becoming more regulated
avoiding the need to use it as such, especially in high-pressure
reactors. Carbonylation of bromobenzene 7 was performed
using compound 8 as the CO source following our previously
described protocol and reaction conditions: 175 1C for 5 minutes
in a 2 mL coil reactor. The resulting tricholorophenylester was
not isolated and further mixed with amine 2a and LHMDS
solutions by means of two consecutive syringe pumps and
T-mixers, allowing them to react for 2 minutes in a 2 mL coil
reactor (Fig. 2). The outcome of the amidation step was
quenched to get 3a in 65% yield after the workup, proving the
value of the protocol in the preparation of challenging hetero-
a
Chart 2 Exploration of the amine scope.
3.3 equiv. of LiHMDS.
b
c
d
Reaction carried out at 50 1C. 1.1 equiv. of LHMDS. Solvent THF.
only at 50 1C. Encouraged by the interesting results using cyclic amides from aryl halides in one cascade event.
(hetero)aromatic amines, the applicability of the reaction A novel protocol for the formation of amides from low
protocol to aliphatic amines was then investigated. They proved nucleophilic heterocyclic amines and esters is described. The
however to be less reactive, and compounds 3r and 3s were only combination of LHMDS, a strong non-nucleophilic base, with
obtained in acceptable yields when the reaction was carried out continuous flow techniques allows for the preparation of these
at 50 1C. This notable observation can be understood from the amides under very mild conditions and in short reaction times,
fact that aliphatic amines are generally less acidic than their by just combining all reagents at the mixing point. The procedure
aromatic counterparts, and hence their deprotonation was is compatible with alkyl and aryl esters and tolerant to different
probably not fully achieved using LHMDS. In these examples functional groups present in both building blocks, especially
full deprotonation was achieved using the complementary those sensitive to the use of alkyllithium and Grignard reagents.
Grignard reagents as the base.8 Furthermore, this new procedure Furthermore, it is perfectly compatible with our previously
Fig. 2 Experimental set-up of the combination of carbonylation and amide formation in line.
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The authors express their appreciation to Prof. Antonio de
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