Direct amide formation from unactivated carboxylic acids and amines

Article abstract of DOI:10.1039/c1cc15210f

The direct coupling of unactivated carboxylic acids with amines can be performed in toluene 110 °C in the absence of catalyst. The use of simple zirconium catalysts at 5 mol% loading gave amide formation in as little as 4 h.

Full text of DOI:10.1039/c1cc15210f

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COMMUNICATION
Direct amide formation from unactivated carboxylic acids and aminesw
C. Liana Allen, A. Rosie Chhatwal and Jonathan M. J. Williams*
Received 22nd August 2011, Accepted 8th November 2011
DOI: 10.1039/c1cc15210f
The direct coupling of unactivated carboxylic acids with amines
can be performed in toluene 110 8C in the absence of catalyst.
The use of simple zirconium catalysts at 5 mol% loading gave
amide formation in as little as 4 h.
60% conversion into N-benzyl-4-phenylbutyramide after heating
4-phenylbutyric acid and benzylamine in toluene at reflux for
22 h in the presence of 3 A molecular sieves.21
Most recently, Whiting et al. have published a detailed study
into the reaction mechanism by which direct amide bond
formation may occur in non-polar, aprotic solvents.22 The
nature of the carboxylic acid interaction with amines was
assessed through computational and experimental evidence,
but only a few examples of direct coupling reactions were given.
In the course of our own studies into developing efficient
amide bond forming reactions,23–27 we became interested in
exploring the direct condensation of carboxylic acids and
amines at lower temperatures than those reported. Since the
formation of charged species is disfavored in non-polar solvents,
we anticipated that salt formation would be disfavored
(Scheme 1). We therefore reasoned that direct amide formation
would be more facile in non-polar solvents and attempted the
coupling of 3-phenylpropanoic acid with 4-methylbenzylamine
in a variety of solvents. We were pleased to find that the direct
uncatalyzed reaction can be performed effectively in some
solvents. In particular, toluene stood out as an excellent solvent
for the uncatalyzed direct formation of amides (see Supporting
Informationw), while no reaction was observed when the reaction
was performed in water. Increasing the concentration of the
reaction run in toluene to 2.0 M allowed complete conversion
into product after 20 h at reflux. The reaction was performed
in a sealed vessel with no molecular sieves, demonstrating that
the equilibrium is favorable without the need to remove water.
We then wanted to identify catalysts which would further
improve reaction rate. We reacted 3-phenylpropionic acid with
benzylamine in toluene at reflux for just 4 h in the presence of a
series of potential catalysts (Table 1). Under these conditions,
the uncatalyzed reaction proceeded to 20% conversion. We
were pleased to find that FeCl2, ZrCl4, CuBr, Ni(NO3)2 and
TiCl4 all led to full conversion in this time. With a catalyst
loading of 5 mol%, the best result was achieved using ZrCl4,28
which gave 83% conversion after 4 h. The use of alternative
The formation of amide bonds is of great importance to many
areas of chemistry. Catalytic amide formation was recently
highlighted as a reaction of importance from a ‘green chemistry’
perspective.1 Many groups, including our own, have been
interested in developing efficient, catalytic methods to form
amide bonds from various starting materials.2
The direct condensation reaction carboxylic acids with
amines to form amides is highly desirable due to the availability
of these compounds and the relative cleanliness of such a
process—the only side product being water. Although reported
as early as 1902,3 the direct coupling reaction has been largely
unoptimized as it is traditionally thought to need very high
temperatures (4180 1C) to overcome ammonium carboxylate
salt formation.4,5 Alternative approaches using coupling reagents6
and stoichiometric reagents7–9 have been developed to activate
a carboxylic acid towards nucleophilic attack; however, these
all produce a stoichiometric amount of waste by-product.
Catalytic methods that have been reported for the direct
coupling of carboxylic acids and amines have generally involved
the use of arylboronic acids and their derivatives,10–12 although
other catalysts have also been reported.13–15 Typically, water is
removed under the reaction conditions in order to drive the
equilibrium towards amide formation. N-Formylations (using
formic acid) have received more attention and several metal
catalysts have been reported for this reaction.2 Microwaves
have also been employed in the direct coupling reaction.16–18
Direct uncatalyzed formation of amides has also been
observed as a background reaction in studies of catalytic amide
formation. In 1989, Cossy reported the synthesis of a small
range of amides at 140 1C under neat conditions in the presence
of 4 A molecular sieves19 and a later report by Gooßen et al.
showed a larger range of amides could be formed under solvent
free thermal conditions at a temperature of 160 1C, again in the
presence of molecular sieves.20 In 2006, Whiting et al. observed
Department of Chemistry, University of Bath, Claverton Down, Bath,
BA2 7AY, U.K. E-mail: j.m.j.williams@bath.ac.uk;
Fax: +44 1225 386231; Tel: +44 1225 383942
w Electronic supplementary information (ESI) available: Additional
experimental information and full characterization and NMR spectra
of isolated compounds. See DOI: 10.1039/c1cc15210f
Scheme 1 Overcoming salt formation by the use of non-polar solvent.
c
666 Chem. Commun., 2012, 48, 666–668
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Table 1 Identification of catalysts for direct amide bond formationa
Catalyst loading (mol%) Conversion (%)b
conversion was seen with just 5 mol% ZrCl4 (42% with catalyst
compared with 7% without—see Supporting Informationw).
We were pleased to find that in all cases, the zirconium catalyst
significantly accelerated the reaction (Table 2). 3-Phenylpropionic
acid reacted well with a range of amines to give the corresponding
amides (Table 2, entries 1–7). Benzylamine was converted into a
range of amides by coupling with carboxylic acids (Table 2,
entries 7–11). Functional groups were tolerated by the reaction
conditions, including heterocycles (Table 2, entries 4, 6, 12, 13
and 17), halogens (Table 2, entries 10 and 17) and unsaturated
groups (Table 2, entry 14). The relatively mild conditions allowed
ketone (Table 2, entry 12), nitrile (Table 2, entry 14) and even
ester groups (Table 2, entry 15) to remain unaffected. N-Boc
glycine, N-Boc proline and valine methyl ester were successfully
converted into secondary amides without loss of the protecting
groups (Table 2, entries 8, 13 and 15). Pleasingly, there was no
racemisation in the prolinamide product.
Entry Catalyst
1
2
3
4
5
6
7
8
No catalyst
FeCl2
ZnCl2
ZrCl4
CuBr
Ni(NO3)2
Al(OiPr)3
Ti(OiPr)4
TiCl4
Sc(OTf)3
HCl
N,N-Diphenylurea 20
ZrCl4
FeCl2
TiCl4
ZrCp2Cl2
Zr(acac)2
20
20
20
20
20
20
20
20
20
20
20
20
100
18
100
100
100
30
63
100
14
30
51
83
35
26
100
77
9
10
11
12
13
14
15
16
17
5
5
5
5
5
a
Conditions: 3-Phenylpropionic acid (1 mmol), benzylamine (1 mmol),
toluene (1 mL), catalyst (20 mol% or 5 mol%), 110 1C, 4 h;
Determined by H NMR spectroscopy.
Aniline was the least reactive amine substrate tested
(presumably due to its relatively lower nucleophilicity), with
only 45% conversion seen even when using the more active
ZrCp2Cl2 catalyst (Table 2, entry 5). Benzoic acid was also less
reactive (Table 2, entry 9). The rate of reaction of benzoic acid
was found to be greatly accelerated using ZrCp2Cl2 as the
catalyst, as after 22 h, there was 83% conversion into secondary
amide, compared with only 6% background rate. The use of
either 4-nitrobenzoic acid or 4-(dimethylamino)benzoic acid,
led to minimal conversion, even in the presence of catalyst.
We applied the reaction to the synthesis of two simple
pharmaceutical drugs; the analgesic paracetamol and the
anti-depressant moclobemide (Table 2, entries 16 and 17).
As the paracetamol synthesis required an aniline as a reacting
partner and the moclobemide synthesis required a benzoic
acid, the reactions were run for 24 h and were pleased to find
b
1
zirconium catalysts did not lead to improvement of this result,
except for Cp2ZrCl2, which gave full conversion to product
after 4 h. Hydrochloric acid (Table 1, entry 11) only had a
weak catalytic effect, indicating that it is not degradation of
the catalyst to HCl which provides catalytic activity. Interest-
ingly, N,N-diphenylurea (Table 1, entry 12) had some catalytic
effect, presumably by acting as a hydrogen bond donor.
We chose to investigate the use of Cp2ZrCl2 and ZrCl4 as
catalysts as these were the most efficient at the lower catalyst
loading and the most selective for secondary amide formation
(CuBr and Ni(NO3)2 led to imine and aldehyde by-products at
lower catalyst loadings). There is a clear rate enhancement when
a zirconium catalyst is present; after 1 h, a six-fold increase in
Table 2 Direct uncatalyzed and catalyzed formation of amidesa
Entry
1
Amide
Conversion(%)b neat
58
Conversion (%)b in toluene
100 (81)
Catalyst
ZrCp2Cl2
ZrCl4
Time (h)
Conversion (%)b
100 (94)
4
5
100 (92)
2
49
84 (72)
ZrCp2Cl2
ZrCl4
4
86 (60)
10
100 (89)
3
4
5
51
18
100 (94)
100 (92)
ZrCl4
10
10
81 (71)
ZrCl4
100 (91)
9
30
73 (150 1C)c
ZrCp2Cl2
24
24
45
37
48 (150 1C)c
ZrCl4
d
6
39
67
ZrCp2Cl2
ZrCl4
24
18
100 (88)
72
51 (150 1C)c
100 (94) (150 1C)c
7
8
79
27
100 (90)
71
ZrCl4
ZrCl4
5
100 (81)
91 (80)
22
c
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Chem. Commun., 2012, 48, 666–668 667

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Table 2 (continued )
Entry
9
Amide
Conversion(%)b neat
o1
28 (150 1C)c
Conversion (%)b in toluene
Catalyst
Time (h)
Conversion (%)b
6
ZrCp2Cl2
22
24
83 (72)
55
44 (150 1C)c
ZrCl4
d
10
11
56
61
58
100 (90)
100 (92)
82 (78)
ZrCl4
ZrCl4
5
5
100 (91)
100 (91)
89 (78)
12
13
ZrCl4
ZrCl4
10
22
0
0
64 (56)
0 (150 1C)c
79 (150 1C)c
499% ee
14
0
84 (76)
ZrCl4
16
93 (84)
15e
16
81
92 (88)
37
ZrCl4
12
24
100 (81)
100 (88)
0
ZrCp2Cl2
0 (150 1C)c
69 (150 1C)c
17
0
14
66 (150 1C)c
ZrCp2Cl2
24
100 (85)
49 (150 1C)c
For additional examples see Supporting Information; Determined by 1H NMR analysis, isolated yields shown in parentheses where appropriate;
a
b
c
d
e
Reactions run at 150 1C were performed in xylenes; Run with 10 mol% catalyst; Run with 1 equivalent N,N-diisopropylethylamine.
that 100% conversion was achieved in both cases, compared
with the uncatalyzed rates which gave 37% conversion for
paracetamol and only 14% conversion for moclobemide
(at 110 1C).
The reversibility of this reaction was tested by reacting
N-benzyl-4-chlorobenzamide with water under the standard
reaction conditions. In the absence of catalyst, no hydrolysis was
seen and with 5 mol% ZrCl4 only 5% hydrolysis was observed.
The scalability of the uncatalysed reaction was assessed by
performing the reaction of 3-phenylpropionic acid and benzyl-
amine on a 400 mmol scale. After 28 h, 100% conversion into
the amide was achieved and the product isolated in 93% yield
(93 g) after recrystallisation.
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c
668 Chem. Commun., 2012, 48, 666–668
This journal is The Royal Society of Chemistry 2012