Zirconium catalyzed amide formation without water scavenging

Article abstract of DOI:10.1002/aoc.5062

A scalable homogeneous metal-catalyzed protocol for direct amidation of carboxylic acids is presented. The use of 2–10?mol% of the commercially available Zr(Cp)₂(OTf)₂·THF results in high yields of amides at moderate temperature, using an operationally convenient reaction protocol that circumvents the use of water scavenging techniques.

Full text of DOI:10.1002/aoc.5062

Received: 11 February 2019
DOI: 10.1002/aoc.5062
Revised: 22 May 2019
Accepted: 23 May 2019
C O M M U N I C A T I O N
Zirconium catalyzed amide formation without water
scavenging
Helena Lundberg1
| Fredrik Tinnis2
| Hans Adolfsson3
1 Department of Chemistry, Division of
Organic Chemistry, Royal Institute of
Technology, SE‐10044 Stockholm, Sweden
A scalable homogeneous metal‐catalyzed protocol for direct amidation of car-
boxylic acids is presented. The use of 2–10 mol% of the commercially available
Zr(Cp)2(OTf)2·THF results in high yields of amides at moderate temperature,
using an operationally convenient reaction protocol that circumvents the use
of water scavenging techniques.
2 Department of Organic Chemistry,
Stockholm University, Arrhenius
Laboratory, SE‐10691 Stockholm, Sweden
3 Department of Chemistry, Umeå
University, SE‐90187 Umeå, Sweden
KEYWORDS
Correspondence
mides, amines, carboxylic acids, catalysis, direct amidation, trifluoromethanesulfonate, zirconium
Helena Lundberg, Department of
Chemistry, Division of Organic Chemistry,
Royal Institute of Technology, SE‐10044
Stockholm, Sweden.
Email: hellundb@kth.se
Hans Adolfsson, Department of
Chemistry, Umeå University, SE‐901 87
Umeå, Sweden.
Email: hans.adolfsson@umu.se
1 | INTRODUCTION
formation of ammonium carboxylate salt is considered
one of the main challenges (Scheme 1).
The amide functionality is one of the most fundamental
chemical units that constitutes the backbone of proteins
and is found in synthetic products such as pharmaceuti-
cals, polymers and agrochemicals.[1] Commonly, amides
are formed with the use of stoichiometric coupling
reagents to activate and protect the carboxylic acid. As a
result, these processes display low atom economy and
green methodologies for the transformation have been
determined as a key green research area by the ACS
Pharmaceutical Roundtable in both 2007 and 2018.[2]
Catalytic condensation of carboxylic acids and amines to
form amides is a highly sustainable reaction, since one
equivalent of water is formed as the sole by‐product.
Despite the atom efficiency, the number of catalytic
protocols for this transformation is limited[3] and the
Typically, catalysts for direct amidation are Lewis
acidic compounds based on boron or transition metals.[4]
In the latter class, Group (IV) metal complexes constitute
the most well‐documented catalyst type.[5] A frequent
complication of homogeneous catalytic direct amidation
is that the generated water deactivates the catalyst
and/or reactive intermediates. For this reason, water
scavenging techniques such as azeotropic distillation or
addition of molecular sieves are commonly employed,
where the latter find their use in mild protocols at low
reaction temperatures. Although convenient enough on
a laboratory scale, the need to continuously remove water
using molecular sieves is a major drawback from a
scale‐up perspective. For this reason, robust and water
tolerant amidation catalysts are of high importance to
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2019 The Authors Applied Organometallic Chemistry Published by John Wiley & Sons Ltd
Appl Organometal Chem. 2019;e5062.
wileyonlinelibrary.com/journal/aoc
1 of 5
https://doi.org/10.1002/aoc.5062

2 of 5
LUNDBERG ET AL.
complexes under non‐dry conditions. Hence, a series of
commercially available metal triflate compounds were
evaluated as catalysts for the condensation of
phenylacetic acid 1a and benzylamine 2a, using the
same solvent and reaction temperature that was previ-
ously employed using ZrCl4 in catalytic amounts.[5d]
Gratifyingly, it was found that both Hf(OTf)4 and
Zr(Cp)2(OTf)2·THF were catalytically active (Table 1,
entries 6 and 7), resulting in approximately 50% yield
after 72 hours. For comparison, ZrCl4 was evaluated
under the same conditions and reaction time, resulting
in 17% yield (Table 1, entry 9). This result is similar to
that obtained in the absence of any catalyst (Table 1,
entry 10) and indicates that the catalytic ability of the
zirconium chloride complex is hampered by the water
formed in the reaction, in contrast to the metallocene
triflate compounds. The higher solubility in organic
medium and the lower molecular weight of the
zirconocene complex compared to the hafnium com-
pound prompted us to continue our study using the for-
mer as catalyst.
SCHEME 1 A carboxylic acid and an amine can condense to an
amide and water or form an ammonium carboxylate salt
enable catalytic formation of amides under mild homoge-
neous conditions. Trifluoromethanesulfonate (triflate,
OTf) complexes of rare earth metals are a class of cata-
lysts that meet these requirements and have been
employed for a variety of reaction types.[6] Recently, the
work of Li et al. demonstrated that polyfluorinated
alkylsulfonate complexes of zirconium were able to acti-
vate carboxylic acids, nitriles and primary amides to
afford secondary amide products under non‐dry condi-
tions.[7] However, a significant limitation of Li′s protocol
is the use of perfluorooctanesulfonate (PFOS) counter-
ions. PFOS is listed as a persistent organic pollutant
(POP) under the Stockholm Convention and is regulated
under the European Chemicals Regulation (REACH EC
No. 1907/2006) and other international regulations due
to its persistent nature, and bioaccumulative and toxic
properties.[8] In contrast, the considerably smaller triflate
unit displays no such restrictions.
In analogy with previously reported Group IV metal‐
catalyzed amidation protocols,[5a,9] excess amine was ben-
eficial for the reaction outcome and enabled a decrease in
catalyst loading (see Supporting Information). As a result,
94% yield was observed in 48 hrs using 2 mol% catalyst
and starting concentrations of 0.4 M and 0.8 M for 1a
and 2a, respectively (Table 1, entry 8). In the absence of
catalyst, thermal amidation resulted in 16% yield of 3a
2 | EXPERIMENTAL
Phenylacetic acid 1a (0.5 mmol) and Zr(Cp2(OTf)2·THF
(5.9 mg, 0.01 mmol, 2 mol %) were added to an oven dried
10 ml microwave tube equipped with a magnetic stir bar
and sealed with a crimp‐on cap with septum. The atmo-
sphere was exchanged for N2 by three consecutive vac-
uum cycles after which THF (1.25 ml) was added. The
reaction mixture was heated to 70 °C in an oil bath,
benzylamine 2a (1 mmol) was added and the reaction
was stirred for 48 hrs. The crude reaction mixture was
filtered through a pad of silica (~15 g) in a glass filter fun-
nel, rinsed with 100 ml ethyl acetate:triethylamine (20:1
mixture) and concentrated under vacuum to afford amide
TABLE 1 Evaluation of amidation catalysts in the absence of
water scavengera
Entry
Catalyst
Mol%
Time (h)
3ac (%)
1a
La(OTf)3
Yb(OTf)3
Y(OTf)3
LiOTf
10
10
10
10
10
10
10
2
108
108
108
72
<5
<5
<5
<5
<5
49
49
94
17
12
16
2a
1
3a
4a
3a in 94% yield. H‐NMR (400 MHz, CDCl3) δ 7.22–7.38
(m, 8 H), δ 7.15–7.20 (m, 2 H), δ 5.66 (bs, 1 H), δ 4.42
(d, J = 5.9 Hz, 2 H), δ 3.64 (s, 2 H). 13C‐NMR
(100 MHz, CDCl3) δ171.0, 138.3, 134.9, 129.6, 129.2,
128.8, 127.6, 127.6, 127.5, 44.0, 43.7.
5a
Ba(OTf)3
Hf(OTf)4
ZrCp2(OTf)2·THF
ZrCp2(OTf)2·THF
ZrCl4
72
6a
72
7a
72
8b
9a
48
3 | RESULTS AND DISCUSSION
10
‐
72
10a
11b
‐
72
We have previously reported that chloride complexes
based on hafnium,[5a] zirconium[5b,d] and titanium[5c]
are active as direct amidation catalysts in the presence
of molecular sieves at 27–70 °C, and were interested in
studying the activity of the corresponding triflate
‐
‐
48
a[1a] and [2a] = 0.1 M, 70 °C, THF, N2 atmosphere.
b[1a] = 0.4 M, [2a] = 0.8 M, 70 °C, THF, N2 atmosphere.
cisolated yield.

LUNDBERG ET AL.
3 of 5
under otherwise identical conditions (Table 1, entry 11).
A decrease in reaction temperature from 70 °C to 50 °C
resulted in lower yield of 3a after 72 hrs (95 and 51%,
respectively, see Supporting Information). High yields of
3a were observed under normal atmosphere using non‐
dried THF (85% yield after 72 hr), however accompanied
by the formation of imine 4a, resulting in a less clean
reaction. For this reason, dry and inert conditions were
henceforth used. Oxidative dimerization of 2a to form
dibenzylimine 4a is a known reaction (Scheme 2) and
has previously been reported to be mediated by catalysts
based on e.g. cobalt,[10] copper[11] and ruthenium.[12] Full
conversion of 1a into 3a was observed as monitored by
HPLC for standard conditions with and without addition
of molecular sieves or one equivalent of water after
72 hours. Addition of molecular sieves resulted in a faster
reaction rate, whereas addition of 5 and 10 equivalents of
water slowed down the rate considerably (see Supporting
Information).
SCHEME 3 Competition experiments
I
O
O
O
(a)
Bn
Bn
Bn
Bn
N
N
N
H
H
H
3c, 67%
3a, 92% (2 equiv. amine)
(10 mmol, reflux rb flask)
74% (2 equiv. acid)
3b, 72%
(2 equiv. amine)
(4 equiv. amine), 72h
O
O
H
O
Bn
H
N
N
H
N
Bn
Bn
Cbz
N
Boc
N
H
H
3e, 85%
3f, 64%
3d, 89%
(4 equiv. amine)
(2 equiv. amine)
(8 equiv.amine)
O
O
We have previously reported that alcohols inhibit Hf‐
and Zr‐catalyzed amidation.[5a,d] Interestingly, this phe-
nomenon was not observed using Zr(Cp)2(OTf)2·(THF)
as demonstrated by a competition experiment using
two equivalents of benzylamine 2a and benzyl alcohol
5a. The reaction proceeded with full selectivity towards
O
Bn
Bn
N
N
H
H
Bn
N
11
H
MeO
O2N
3h, 11/27% (48/120h)
(8 equiv. amine)
3i, 91%
3g, 26/50% (48/120h)
(8 equiv. amine),
(4 equiv. amine)
O
O
O
O
N
S
Bn
N
Bn
N
N
H
N
N
H
amide product with
a 56% yield after 48 hours
3l, 66%, 100oC
(2 equiv. amine)
3j, 99%
(2 equiv. amine)
3k, 94%
(2 equiv. amine)
N
(Scheme 3A). Furthermore, the catalyst was found to
favor amidation of carboxylic acids over esters
O
O
(b)
(Scheme 3B).
A competition experiment using p‐
Bn
N
Ph
Bn
N Ph
H
H
tolylacetic acid 1b and ethylphenylacetate 6b in the
presence of 2a resulted in 82% yield of 3b
compared to 32% yield of 3a. Similar selectivity was
observed in hafnium‐catalyzed amide formation at
room temperature,[5a] while efficient zirconium‐
catalyzed aminolysis of esters at 100 °C has previously
been reported.[13]
3a, 92% (2 equiv. amine)
3m, 46% (8 equiv. amine)
(10 mmol, reflux rb flask)
O
H
O
H
N
Bn
N
Bn
Cbz
N
Cbz
N
H
H
3n,15% (4 equiv. amine)
3d, 89% (4 equiv. amine)
Conditions: [acid] = 0.4 M, 70 °C, THF, N2 atmosphere, 48h.
FIGURE 1 Substrate evaluation
An evaluation of the substrate scope was carried out,
demonstrating that the protocol works well with both
benzylic and aliphatic amines (Figure 1A). The reaction
also proceeded smoothly using heteroaromatic amines
(3j and 3 k), whereas aromatic amines failed to form
product. Secondary aliphatic amines reacted sluggishly
under standard conditions; however, by increasing the
reaction temperature to 100 °C the nitrogen‐rich amide
3l was isolated in 66% yield. The reaction proved to be
scalable from 0.5 mmol to 10 mmol without problems,
affording amide 3a in 92% isolated yield using a round‐
bottomed flask and reflux condenser. An iodo‐substituted
carboxylic acid was also smoothly converted into its cor-
responding benzyl amide 3b in good yield, with the
halide serving as a useful handle for further functional
group manipulations. Both Cbz and Boc protecting
groups are compatible with the reaction conditions
(3d‐e) whereas Fmoc‐protected glycine resulted in trace
amounts of amide product. Aromatic acids reacted slug-
gishly even in the presence of a large excess of 2a and
extended reaction times with benzoic acid giving rise to
higher yields compared to analogues with either electron
withdrawing or donating substituents (3f‐h). This finding
stands in contrast to the previously reported protocol cat-
alyzed by ZrCl4, where electron‐poor benzoic acids
reacted faster than more electron‐rich analogues.[9]
[ox]
Ph
N
Ph
2
Ph
NH2
2a
4a
SCHEME 2 Oxidative by‐product formation of imine 4a under
non‐inert conditions

4 of 5
LUNDBERG ET AL.
Although unexpected, this difference does not necessarily
indicate different operating mechanisms between the dry
and the non‐dry Zr‐catalyzed protocols and may result
from differences in equilibria of ammonium carboxylate
salts and/or other off‐cycle species.
REFERENCES
[1] New address: F. Tinnis, Ardena, Box 2073, S‐151 02 Södertälje,
Sweden
[2] a) D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey,
J. J. L. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A.
Pearlman, A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007,
9, 411; b) M. C. Bryan, P. J. Dunn, D. Entwistle, F. Gallou, S.
G. Koenig, J. D. Hayler, M. R. Hickey, S. Hughes, M. E.
Kopach, G. Moine, P. Richardson, F. Roschangar, A. Steven,
F. J. Weiberth, Green Chem. 2018, 20, 5082.
As demonstrated in Figure 1B the reaction is sensi-
tive towards steric hindrance in both the amine and
the carboxylic acid. Even in the presence of 8 equiva-
lents of amine, amide 3m was isolated in only 46% yield
as compared to 92% of amide 3a after the same reaction
time. Similarly, amide 3d was isolated in 91% yield
whereas amide 3n was isolated in merely 15% yield.
The observed drop in yield for the substrates with a
methyl group in the neighbouring position of either
the carboxylic acid or amine compared to their H‐
analogues is analogous to the previously reported
hafnium‐ and zirconium‐catalyzed protocols under dry
conditions.[5a, d]
[3] a) M. T. Sabatini, L. T. Boulton, H. F. Sneddon, T. D. Sheppard,
Nature Catal. 2019, 2, 10; b) X. Wang, Nature Catal. 2019, 2, 98;
c) R. M. de Figueiredo, J.‐S. Suppo, J.‐M. Campagne, Chem.
Rev. 2016, 116, 12029; d) A. Ojeda‐Porras, D. Gamba‐Sánchez,
J. Org. Chem. 2016, 81, 11548; e) H. Lundberg, F. Tinnis, N.
Selander, H. Adolfsson, Chem. Soc. Rev. 2014, 43, 2714; f) B.
M. Monks, A. Whiting, Sustainable Catalysis, John Wiley &
Sons, Inc., Hoboken, New Jersey, USA 2013, 89; g) C. L. Allen,
J. M. Williams, J. Chem. Soc. Rev. 2011, 40, 3405; h) T. Krause,
S. Baader, B. Erb, L. J. Gooßen, Nat. Commun. 2016, 7, 11732; i)
L. Hu, S. Xu, Z. Zhao, Y. Yang, Z. Peng, M. Yang, C. Wang, J.
Zhao, J. Am. Chem. Soc. 2016, 138, 13135; j) X. Xu, H. Feng, L.
Huang, X. Liu, J. Org. Chem. 2018, 83, 7962; k) L. Hu, J. F.
Zhao, Synlett 2017, 28, 1663; l) S. M. Akondi, P. Gangireddy,
T. C. Pickel, L. S. Liebeskind, Org. Lett. 2018, 20, 538; m) V.
Srivastava, P. K. Singh, P. P. Singh, Tetrahedron Lett. 2019,
60, 40.
4 | CONCLUSIONS
To conclude, a practical and scalable homogeneous
protocol for direct amidation using a commercially
available zirconium catalyst has been developed that
circumvents the use of water scavenging techniques.
The system shares several characteristics with previously
developed Group (IV) metal‐catalyzed protocols for direct
amidation, such as higher yields using higher amine con-
centrations and a preference for amidation of carboxylic
acids over esters. The tolerance towards alcohols and
stoichiometric quantities of water are however distinct
differences of this system compared to previous protocols.
Group (IV) metal chloride complexes are known to be
hydrolytically unstable and form the corresponding
oxides in the presence of water. The observation that
fluorosulfonate analogues of water‐sensitive chloride
complexes can be used as catalysts under non‐dry condi-
tions is intriguing and makes these Lewis acidic metal
compounds a highly interesting class of robust catalysts
for further exploration.
[4] For selected examples of boron‐based amidation catalysts and
mediators see: a) Y. Du, T. Barber, S. E. Lim, H. S. Rzepa, I.
R. Baxendale, A. Whiting, Chem. Commun 2019, 55, 2916; b)
D. N. Sawant, D. B. Bagal, S. Ogawa, K. Selvam, S. Saito, Org.
Lett. 2018, 20, 4397; c) M. T. Sabatini, L. T. Boulton, T. D.
Sheppard, Sci. Adv. 2017, 3, e1701028; d) H. Noda, M.
Furutachi, Y. Asada, M. Shibasaki, N. Kumagai, Nat. Chem.
2017, 9, 571; e) T. Mohy El Dine, W. Erb, Y. Berhault, J.
Rouden, J. Blanchet, J. Org. Chem. 2015, 80, 4532; f) R. M.
Lanigan, P. Starkov, T. D. Sheppard, J. Org. Chem. 2013, 78,
4512; g) N. Gernigon, R. M. Al‐Zoubi, D. G. Hall, J. Org. Chem.
2012, 77, 8386; h) K. Arnold, B. Davies, D. Herault, A. Whiting,
Angew. Chem. Int. Ed. 2008, 47, 2673; i) K. Arnold, B. Davies, R.
L. Giles, C. Grosjean, G. E. Smith, A. Whiting, Adv. Synth.
Catal. 2006, 348, 813; j) K. Ishihara, S. Ohara, H. Yamamoto,
J. Org. Chem. 1996, 61, 4196.
[5] a) H. Lundberg, H. Adolfsson, ACS Catal. 2015, 5, 3271; b) F.
Tinnis, H. Lundberg, H. Adolfsson, Adv. Synth. Catal. 2012,
354, 2531; c) H. Lundberg, F. Tinnis, H. Adolfsson, Synlett
2012, 2201; d) H. Lundberg, F. Tinnis, H. Adolfsson, Chem. A
Eur. J. 2012, 18, 3822; e) C. L. Allen, A. R. Chhatwal, J. M. J.
Williams, Chem. Commun. 2012, 48, 666; f) L. Y. Shteinberg,
S. A. Kondratov, S. M. Shein, Zh. Org. Khim. 1988, 24, 1968;
g) L. Y. Shteinberg, S. A. Kondratov, S. M. Shein, Zh. Org.
Khim. 1989, 25, 1945.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Stockholm
University, the K. & A. Wallenberg Foundations and the
Swedish Research Council for financial support.
[6] a) S. Kobayashi, C. Ogawa, Chem. A Eur. J. 2006, 12, 5954; b)
T.‐P. Loh, G.‐L. Chua, Chem. Commun. 2006, 2739; c) M. U.
Kahveci, M. A. Tasdelen, W. D. Cook, Y. Yagci, Macromol.
Chem. Phys. 2008, 209, 1881; d) N. A. Rebacz, P. E. Savage,
Ind. Eng. Chem. Res. 2010, 49, 535; e) N. A. Rebacz, P. E. Sav-
age, Phys. Chem. Chem. Phys. 2013, 15, 3562; f) K. Tekin, M.
ORCID
Helena Lundberg https://orcid.org/0000-0002-4704-1892
Fredrik Tinnis https://orcid.org/0000-0003-1271-4601
Hans Adolfsson https://orcid.org/0000-0001-5887-4630

LUNDBERG ET AL.
5 of 5
K. Akalin, S. Karagöz, J. Energy Inst. 2016, 89, 627; g) M. de
Léséleuc, S. K. Collins, ACS Catal. 2015, 5, 1462; h) M. de
Léséleuc, S. K. Collins, Chem. Commun. 2015, 51, 10471.
[13] C. Han, J. P. Lee, E. Lobkovsky, J. A. Porco, J. Am. Chem. Soc.
2005, 127, 10039.
[7] N. Li, L. Wang, L. Zhang, W. Zhao, J. Qiao, X. Xu, Z. Liang,
SUPPORTING INFORMATION
ChemCatChem 2018, 10, 3532.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[8] a) R. Renner, Environ. Sci. Technol. 2001, 35, 154A; b) S.
Brendel, E. Fetter, C. Staude, L. Vierke, A. Biegel‐Engler,
Environ. Sci. Eur. 2018, 30, 9.
[9] H. Lundberg, F. Tinnis, J. Zhang, A. G. Algarra, F. Himo, H.
Adolfsson, J. Am. Chem. Soc. 2017, 139, 2286.
[10] a) S. Zhao, C. Liu, Y. Guo, J.‐C. Xiao, Q.‐Y. Chen, J. Org. Chem.
2014, 79, 8926; b) S. Hazra, P. Pilania, M. Deb, A. K.
Kushawaha, A. J. Elias, Chem. A Eur. J. 2018, 24, 15766.
How to cite this article: Lundberg H, Tinnis F,
Adolfsson H. Zirconium catalyzed amide formation
without water scavenging. Appl Organometal
Chem. 2019;e5062. https://doi.org/10.1002/aoc.5062
[11] M. Largeron, M.‐B. Fleury, Angew. Int. Ed. 2012, 51, 5409.
[12] a) A. Prades, E. Peris, M. Albrecht, Organomet. 2011, 30, 1162;
b) Y. Zhang, F. Lu, R. Huang, H. Zhang, J. Zhao, Cat. Com.
2016, 81, 10.