DOI: 10.1002/chem.

201104055

Direct Amide Coupling of Non-activated Carboxylic Acids and Amines

Catalysed by Zirconium(IV) Chloride

Helena Lundberg, Fredrik Tinnis, and Hans Adolfsson*[a]

The amide bond is one of the most important functionali- tion methods. Metal-catalysed aminolysis of esters has also
ties found in nature. It constitutes the backbone of the bio- been reported.[13]
logically crucial peptides and is found in many natural prod- However, the ideal situation is to directly couple carbox-
ucts and the majority of pharmaceutically interesting com- ylic acids with amines producing water as the only by-prod-
pounds.[1] It has been estimated that up to 25 % of all syn- uct. Since this process leads to an initial salt formation,
thetic pharmaceuticals contain at least one amide bond[2] during which the generation of the carbon–nitrogen bond in
and a general protocol for the direct amidation of carboxylic the amide and subsequent release of water has a high
acids is highly attractive for industry because it would lead energy barrier, the use of a catalytic setup would be most
to more cost-effective and greener processes with extraordi- desirable. Up to now, only a few catalytic systems for the
narily high atom economy.[3] The quest for this type of gen- direct amide coupling of carboxylic acids and amines have
eral protocol remains one of the most important challenges been developed. Organocatalytic methods employing en-
in organic chemistry today. zymes[14–16] have been used to some extent, although they
The thermodynamically stable amide bond is, in principle, have a limited substrate scope. Other protocols that use ar-
formed when a carboxylic acid reacts with an amine with ylboronic acids and esters[17–26] as catalysts have been report-
the release of water. The energy threshold of the ammonium ed, although, to the best of our knowledge, without exam-
carboxylate salt formation must, however, be overcome, and ples in which the enantiopurity of chiral starting materials is
a number of synthetic methods for amidation have been de- fully conserved. In some cases the ee even drops significant-
veloped over the years. Direct amidation of carboxylic acids ly, as in the report by Yamamoto et al. in which the amida-
and amines occurs spontaneously at high temperatures tion of enantiopure N-tert-butoxycarbonyl (N-Boc) valine
ACHTUNGRE(>160 8C).[4–8] However, this is not a feasible strategy for resulted in a product with only 81 % ee.[24]
many substrates because sensitive functional groups do not In addition to arylboronic acids, other non-metallic and
survive under such harsh conditions. Milder methods have metallic Lewis acids, including heterogeneous Lewis acidic
therefore been developed, most of which employ stoichio- materials, have been employed as mediators or catalysts for
metric amounts of coupling reagents, such as carbodiimides, the amidation reaction.[27–38] Moreover, early transition-
chloroformate and pyridinium compounds, or uronium, im- metal complexes, like titanium(IV) species, have been found
monium, imidazolium and phosphonium salts.[9, 10] There has to act as mediators. In 1970, Wilson and Weingarten[39] re-
also been an example of an umpolung strategy in which the ported that stoichiometric amounts of TiCl4 in THF mediat-
amine was made electrophilic with the use of N-iodo succi- ed the formation of carboxamides in modest to good yields
nimide.[11] over several days of reaction time. Shteinberg and co-work-
Despite the efficiency of these protocols, they often suffer ers have reported that a catalytic amount of TiACHTUNGRE(OBu)4
from complicated product isolations and poor atom econo- (20 mol %) could be used in the acylation of anilines with
my, and the stoichiometric use of reagents generates high benzoic acids in toluene, ortho-xylene and decane at
costs and a low product to waste ratio.[3] To overcome some reflux.[40, 41] In 1988, Nordahl and Carlson[42] used a catalytic
of these problems, different catalytic methods have also amount of TiCl4 (30 mol %) for the amidation of benzoic
been developed. In the toolbox of the organic chemist, there acid with different amines in toluene at reflux. In the same
are now a number of metal-catalysed protocols[12] for amide year, Mader and Helquist[43] reported TiACHTUNGRE(OiPr)4-mediated
bond formation, utilising starting materials such as nitriles, lactamisations of amino acids in 1,2-dichloroethane at
oximes, aldehydes and alcohols, as well as aminocarbonyla- reflux. Good yields of lactams were achieved with 50 mol %
of TiACHTUNGRE(OiPr)4, although lower yields were obtained with truly
catalytic amounts of the titanium source. Furthermore, they
[a] H. Lundberg, F. Tinnis, Prof. H. Adolfsson reported that only ammonium carboxylate salts were
Department of Organic Chemistry, Stockholm University formed with TiACHTUNGRE(OiPr)4 as the catalyst for intermolecular
The Arrhenius Laboratory, SE-106 91, Stockholm (Sweden)
Fax: (+ 46) 8-154908
amide couplings in a variety of solvents.[44]
E-mail: [email protected] Due to the importance of the amide bond in a vast array
Supporting information for this article is available on the WWW of applications, and the clear lack of a general catalytic pro-
under http://dx.doi.org/10.1002/chem.201104055. tocol for the formation of this functional group, we were in-

3822  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 3822 – 3826
 COMMUNICATION
trigued by the challenge and started to investigate the possi- to as little as 2 mol % while maintaining the activity for the
bility of generating a direct catalytic amidation method model substrate (Table 1 entry 4). Furthermore, we found
starting from carboxylic acids. The aim of the study was to that the reaction was rather insensitive to the stoichiometry
develop a method that, in contrast to the aforementioned of these particular reactants because equally good results
reports, was applicable for a wide range of substrates and were obtained by using either a slight excess of the acid or
could be performed with low catalyst loadings at the lowest of the amine. For the formation of most other amides and
possible temperature. The temperature was an issue for us for reactions in other solvents, the use of an excess of the
mainly due to mildness of the reaction conditions, but also amine component was highly beneficial (see below).
to make sure that the system would be truly catalytic. Since To verify that the amidation reactions are indeed cata-
quantitative conversions can be obtained at 160 8C with lysed by the Lewis acids, experiments were performed with
simple substrates,[4–8] a considerable amount of the amide only molecular sieves present (Table 1, entries 5 and 6).
formed in catalytic reactions run in toluene or ortho-xylene These reactions resulted in 10–13 % yields of the amide de-
heated at reflux can be assumed to be the result of a back- pending on the stoichiometry between the amine and acid
ground reaction. components. The poor outcome of the uncatalyzed reactions
To our delight we found that all examined zirconium com- clearly shows that the high yields in Table 1, entries 1–4 are
plexes were efficient as catalysts for the amidation reaction truly the result of zirconium catalysis. In addition, perform-
(Scheme 1), and isolated yields of up to > 99 % of the ing the zirconium-catalysed amidation without any water
scavengers present resulted in notably reduced yields.
Further optimisation of the reaction conditions was per-
formed by taking different solvents into consideration. The
results show that ethereal solvents are the most effective, al-
though the amidation also works well in other common or-
ganic solvents (Table 1, entry 4 and 7–10). In contrast to the
use of THF, for which the reagent stoichiometry was less
Scheme 1. Zirconium-catalysed amide formation.
sensitive, better yields were obtained if an excess of the
amine was used. Furthermore, it should be stressed that the
successful results with these types of substrates were ob-
formed amide 3 a were obtained with a 10 mol % catalyst tained at markedly lower reaction temperatures than previ-
loading. Since zirconium tetrachloride (Table 1, entry 3) was ously reported by using other Lewis acidic metal catalysts.
found to be the most efficient, as well as the most attractive- The simplicity of this catalytic amidation protocol, for
ly priced ($300 for 1 kg of ZrCl4 as compared to $7680 for which the amine is simply added to an inert mixture of car-
the same amount of ZrACHTUNGRE(OtBu)4 or ZrACHTUNGRE(OEt)4 from Strem boxylic acid, catalyst and molecular sieves in dry THF at
Chemicals Inc., November 2011), we decided to continue 70 8C, is further emphasised by the exceptionally straightfor-
our investigation by using this compound as the catalyst of ward workup needed for the isolation of the products. Ana-
choice. We found that the catalyst loading could be reduced lytically pure samples of amide 3 a were obtained by simple
filtration of the reaction mixture through a pad of silica by
using EtOAc/Et3N (200:1) as the eluent. Moreover, extrac-
Table 1. The zirconium(IV)-catalysed direct amidation of phenyl acetic tive workup of the reaction mixture is equally efficient.
acid with benzylamine. Amide 3 a was prepared as stated above, but, instead of fil-
Entry Catalyst Solvent Catalyst Loading Isolated yield tration through silica, the reaction mixture was filtered
ACHTUNGRE[mol %] [%] through Celite to remove the molecular sieves. The filtrate
1[a] ZrACHTUNGRE(OtBu)4 THF 10 93 was diluted with dichloromethane, extracted with aqueous
2[a] ZrACHTUNGRE(OEt)4 THF 10 93 HCl (1 m) and, after drying and evaporation of the solvent,
3[a] ZrCl4 THF 10 > 99
the analytically pure product was obtained in 96 % yield.
4[a,b] ZrCl4 THF 2 > 99
5[a] – THF – 10 As demonstrated by the results presented in Table 1, sev-
6[b] – THF – 13 eral solvents were compatible with the zirconium catalyst
7[b,c] ZrCl4 1,4-dioxane 2 98 (8) for the amidation reaction. This feature is extremely valua-
8[b,c] ZrCl4 CH2Cl2 2 92 (11)
ble, and opens up the reaction to the use of different sol-
9[b,c] ZrCl4 CH3CN 2 86 (10)
10[b,c] ZrCl4 toluene 2 94 (5) vents for individual substrates, matching their solubility
properties. In this study, we decided to continue with the
[a] Reaction conditions: phenylacetic acid (1.2 mmol), benzyl amine
(1 mmol), catalyst (2 or 10 mol %) and activated 4  molecular sieves fairly non-toxic and low boiling THF as the solvent of
(0.5 g) in dry solvent (amine concentration: 0.4 m) at 70 8C in a sealed choice, and a number of different carboxylic acids and
tube under a N2 atmosphere. Reaction time: 24 h. [b] Reaction condi- amines were screened, employing the amidation protocol
tions: phenylacetic acid (1 mmol), benzyl amine (1.2 mmol), and other- presented above.
wise identical conditions to those given above. [c] The values presented
within parentheses refer to the yield (as determined by using NMR spec-
As shown in Table 2, individual amides were isolated in
troscopy) obtained in the background reaction performed with molecular good to excellent yields. The reaction conditions tolerate
sieves (0.5 g) but without the zirconium catalyst. a significant number of structurally different acid substrates,

Chem. Eur. J. 2012, 18, 3822 – 3826  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3823
 H. Adolfsson et al.

Table 2. Scope of the zirconium chloride-catalysed direct amidation of including heteroaromatic, aliphatic, a-halogenated and
carboxylic acids.[a] a-substituted carboxylic acids, as well as N-protected amino
acids.[45]
To verify that the products are formed through zirconium
catalysis, we performed amidations of all of the substrates
presented in Table 2 without adding the zirconium catalyst.
In the majority of cases examined, the uncatalyzed reaction
resulted in < 10 % yield of the amides and in none of the ex-
amples given in Table 2 was the yield higher than 18 % (see
the Supporting Information).
Ethers and thioethers (3 b and 3 c) are unaffected by the
amidation reaction, and common acid sensitive organic pro-
tecting groups, such as acetals (3 r and 3 w) and carbamates
(3 k–n), remain untouched after the reaction. Chiral enantio-
merically pure N-protected amino acids are converted into
their corresponding amides without racemisation,[45] empha-
sising the mildness of this procedure. The amide formation
by using enantiopure 1-phenylethylamine also occurs with
complete retention of configuration.[46] The zirconium-cata-
lysed amidation reaction is somewhat sensitive towards ster-
ically hindered substrates, and does not work as well with ar-
omatic acids,[47] such as benzoic acid and its derivatives. To
increase the yield of these more difficult substrates (3 d–f)
the amount of catalyst was adjusted to 10 mol % and the re-
action temperature was set at 100 8C. Despite the increase in
the reaction temperature, the yields of the uncatalyzed
background reactions are, in these cases, not higher than
those observed for the other substrates at 70 8C.
The reaction conditions tolerate the use of a variety of
amine reactants for which the use of benzylic or aliphatic
primary amines gives secondary amides in good to excellent
yields. Tertiary amides 3 u–w were formed in good yields by
using 10 mol % ZrCl4 at 100 8C. In addition to the amides
presented in Table 2, we performed a direct zirconium-cata-
lysed amidation on the structurally more complex non-
ACHTUNGREsteroidal anti-inflammatory drug indomethacin (Scheme 2).
The reaction between indomethacin and benzyl amine
smoothly produced the corresponding amide in 97 % isolat-
ed yield.

[a] Reaction conditions: carboxylic acid (1 mmol), amine (1.2 mmol),

Scheme 2. Preparation of N-benzyl indomethacin amide.
ZrCl4 (2–10 mol %), and activated 4  molecular sieves (0.5 g), in dry
THF (amine concentration: 0.4 m) at 70 8C in a sealed tube under a N2 at-
mosphere. Reaction time: 24 h. All compounds (3 a–3 w) were isolated as
analytically pure samples after simple filtration of the reaction mixture The mild and selective zirconium-catalysed amidation
through a plug of silica by using EtOAc/Et3N (200:1) as the eluent. protocol proved easy to scale up, as demonstrated by a gram
[b] 2 mol % ZrCl4 [c] 10 mol % ZrCl4 [d] 5 mol % ZrCl4 [e] Carboxylic
scale experiment in which 20 mmol of (phenylthio)acetic
acid (1.2 mmol), amine (1 mmol). [f] Reaction temperature: 100 8C.
[g] Carboxylic acid (1 mmol), amine (1.5 mmol). Reaction temperature: acid (1 c) and 24 mmol of benzylamine (2 a) were reacted in
100 8C. THF at a concentration of 1.6 m. The reaction resulted in
5.11 g (19.9 mmol, 99 % yield) of analytically pure amide 3 c

3824 www.chemeurj.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 3822 – 3826
Amide Coupling
COMMUNICATION
The formation of zirconium carboxylates would lead to ef-
ficient leaving group activation (Scheme 4 c). Early transi-
tion metals like zirconium have relatively labile ligands that
can easily undergo ligand substitution in solution. The for-
mation of metal–oxygen bonds is favoured for zirconium,
but zirconium–amine complexes can also form. Wilson and
Scheme 3. Gram-scale preparation of amide 3 c. Weingarten[39] put forth the possibility that their titanium-
mediated amidation reaction proceeds through a ligand ex-
change of the original complex with carboxylic acids and
after filtration of the reaction mixture through a silica pad amines. They argue that, if this is the case, more sterically
(Scheme 3). Moreover, the use of a reaction setup in which demanding substrates would probably result in lower yields.
phenyl acetic acid (1 a) and benzyl amine (2 a) were heated That trend also exists for the zirconium-catalysed system de-
at reflux in THF (70 8C) in a dry round-bottomed flask scribed herein, but this tendency is well known for most cat-
equipped with a condenser, under otherwise identical condi- alytic systems and the argument is not conclusive. It is also
tions to those presented in Table 2, resulted in an 89 % iso- possible that a mechanism in which two or more zirconium
lated yield of amide 3 a. The latter example, which was per- ions interact to form a catalytic complex is at work, in anal-
formed on a 40 mmol scale, demonstrates that the catalytic ogy to the amidation mechanism for titanium(IV) butoxide
amidation reaction can productively be performed by using at 145 8C suggested by Shteinberg et al.[51] Future work will
conventional laboratory equipment. In comparison to other shed more light upon the mechanism of the ZrCl4-catalysed
published gram-scale methods, this zirconium-catalysed ami- amide coupling of carboxylic acids and amines, and mecha-
dation protocol has the advantage of being milder, less nistic investigations are currently being pursued.
toxic, and more compatible with different common solvents. To conclude, despite the fact that the formation of amides
For instance, the boric acid catalysed system requires is one of the most performed reactions in the production of
a higher reaction temperature, and results in racemisation of fine chemicals and pharmaceuticals, very few efficient cata-
the chiral starting material when such compounds are em- lytic amidation processes of non-activated carboxylic acids
ployed.[48] Furthermore, the toxicity of boric acid is signifi- have been reported up to now.[52] Furthermore, none of the
cantly higher than that of ZrCl4.[49] existing methods allow full conservation of the enantiomeric
There are several possible mechanisms by which the zirco- purity of the process going from a chiral starting materials
nium-catalysed amidation reaction could proceed. Earlier to the products. Herein, we have presented a novel, mild,
studies on Lewis acid catalysed amidations[31, 41] suggest that versatile, effective and environmentally benign protocol for
the mechanism might proceed through a route similar to direct amidation by using catalytic amounts of inexpensive
that of the catalytic amidation of esters, as proposed by, for zirconium(IV) chloride. This simple and high-yielding
example, Bonora et al.[50] With this view in mind, the activa- method tolerates a wide range of functionalities, including
tion of the carboxylic acid can be envisioned as carbonyl co- acid labile groups, and is suitable for the amidation of both
ordination to zirconium in a classic Lewis acidic fashion simple and more complex starting materials, such as indo-
(Scheme 4 a). In light of the recent study by Whiting et al., methacin. The method conserves the enantiomeric purity of
the possibility of hydrogen-bonded dimeric carboxylic acid the starting materials and is suitable for larger scale synthe-
species cannot be ruled out.[8] Another possibility is simulta- ses, which indicates its usability in research laboratories, as
neous activation of both the carbonyl and the leaving group, well as in industrial applications.
as depicted in Scheme 4 b. In both cases, the acid becomes
electropositive enough for subsequent attack by the amine.
Acknowledgements
We are grateful for financial support from the Swedish Research Council,
the Carl Trygger Foundation and the K & A Wallenberg Foundation.

Keywords: amides · amines · carboxylic acids ·

homogeneous catalysis · zirconium

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3826 www.chemeurj.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 3822 – 3826