ARTICLE

Received 9 Dec 2015 | Accepted 25 Apr 2016 | Published 10 Jun 2016 DOI: 10.1038/ncomms11732 OPEN

Atom-economic catalytic amide synthesis

from amines and carboxylic acids activated
in situ with acetylenes
Thilo Krause1, Sabrina Baader1, Benjamin Erb1 & Lukas J. Gooen1

Amide bond-forming reactions are of tremendous significance in synthetic chemistry.

Methodological research has, in the past, focused on efficiency and selectivity, and these have
reached impressive levels. However, the unacceptable amounts of waste produced have led the
ACS GCI Roundtable to label ‘amide bond formation avoiding poor atom economy’ as the most
pressing target for sustainable synthetic method development. In response to this acute
demand, we herein disclose an efficient one-pot amide coupling protocol that is based on
simple alkynes as coupling reagents: in the presence of a dichloro[(2,6,10-dodecatriene)-1,12-
diyl]ruthenium catalyst, carboxylate salts of primary or secondary amines react with
acetylene or ethoxyacetylene to vinyl ester intermediates, which undergo aminolysis to give
the corresponding amides along only with volatile acetaldehyde or ethyl acetate, respectively.
The new amide synthesis is broadly applicable to the synthesis of structurally diverse amides,
including dipeptides.

1 FB Chemie-Organische Chemie, Technische Universität Kaiserslautern, Erwin Schrödinger Strasse Geb. 54, 67663 Kaiserslautern, Germany. Correspondence

and requests for materials should be addressed to L.J.G. (email: [email protected]).

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ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11732

A
mide bond formation is one of the most frequently two-step procedures with isolation of sensitive enol esters. For
used transformations in organic chemistry1–4. The most example, Kita et al. reported an amide synthesis via isolated
desirable amide synthesis, a direct condensation of ketene acetal intermediates64, and Breinbauer et al. synthesized
carboxylic acids with amines, is hindered by the intrinsic polypeptides via a Ru-catalysed hydroacyloxylation of alkynes
acid–base reactivity of the starting materials. The thermal amide followed by enzymatic aminolysis65. These reactions demonstrate
bond formation from the ammonium carboxylate salts requires the potential of this concept, giving access to amides in high
high temperatures5–7, which can be lowered by Lewis acids or yields under mild conditions, as demanded especially by peptide
boronic acid derivatives. However, even the best known systems chemists. However, this approach can reach synthetic maturity
are limited to a narrow range of amines and require scavenging the only through a catalytic one-pot process that overcomes all its
reaction water, for example, by large amounts of molecular sieves. associated problems, for example, carboxylate salt formation
(Fig. 1, left)8–13. Therefore, amides are usually synthesized by with basic amines which hinders catalytic hydroacyloxylation, the
aminolysis of activated carboxylic acid derivatives, such as halides, control of hydroamination as a side reaction, and the challenging
anhydrides, azides, or activated esters, that are mostly generated in activation of gaseous acetylene, which state-of-the-art catalysts
an extra step with aggressive, expensive or waste-intensive have not been extending to66.
reagents14–20. The other main strategy for amide bond formation We disclose herein an amidation protocol which allows the use
involves the in situ activation of carboxylic acids by peptide of low-molecular acetylene and its more activated homologue
coupling reagents, such as carbodiimides or phosphonium ethoxyacetylene as a sustainable alternative for state-of-the-art
salts21–31. Such amide syntheses are highly optimized and coupling agents. These procedures are convincing in terms of the
provide access to almost any amide structure in near quantitative amount, toxicity and separation of the formed byproducts, yet,
yields. In modern protein synthesis, they are complemented by broadly applicable, convenient and comparable cheap.
efficient chemical and enzymatic peptide ligation methods32–37.
However, the atom economy of all these processes is low, and the Results
cumulative waste generated during amide synthesis is Development of a one-pot amide synthesis. Evaluation of
unacceptable. As a result, the ACS GCI Roundtable has state-of-the-art catalysts, for example, [Ru(methallyl)2dppb] or
identified ‘amide bond formation avoiding poor atom economy’ [RuCl2(PPh3)(p-cymene)]58,67–69, in the reaction between
as the most pressing target for sustainable synthetic method benzoic acid (1a) and 1-hexyne confirmed that they give high
development38. yields only in the absence of benzylamine. None of them catalysed
Over the last years, some elegant strategies for waste-minimized the reaction of 1a with acetylene to give vinyl benzoate
amide synthesis have been devised (Fig. 1), for example, (3a; Supplementary Tables 4 and 5).
dehydrogenative couplings of alcohols, aldehydes or alkynes However, we were pleased to find that simple RuCl3 catalyses
with amines, or additions of alcohols to nitriles39–51. However, the conversion of benzylammonium benzoate (6aa) to the desired
for most synthetic organic chemists, carboxylic acids and amines N-benzyl benzamide in up to 75% yield at 80 °C under acetylene
are still the optimal substrate base for amide synthesis. at 1.7 bar, which is its usual tank pressure (Table 1, entry 1).
To address the central issue of atom economy in the synthesis Systematic evaluation of RuIII and RuIV precursors revealed that
of amides from ammonium carboxylates, we looked for an Ru-1 was most effective (entries 2 and 3). Phosphine and
activator with minimal molecular weight and low intrinsic nitrogen ligands adversely affected the yield (Supplementary
reactivity that would scavenge the reaction water in a catalytic Tables 1 and 2). This is surprising, because the only known RuIV
condensation process. We envisioned that a hydroacyloxylation hydroacyloxylation catalyst is the triphenylphosphine complex
catalyst with unprecedented activity might enable the generation reported by Cadierno et al.70
of vinyl esters from ammonium carboxylates and gaseous Dioxane was found to be the best solvent, but the reaction also
acetylene. Aminolysis of these intermediates would furnish the works well in toluene, THF and ethyl acetate (entries 4  8). The
desired amides along with volatile acetaldehyde. reaction is surprisingly tolerant to oxygen and water up to a
RuII, AgI and AuI complexes efficiently promote the addition certain threshold (Supplementary Table 1).
of carboxylic acids to alkynes under mild conditions, as reported Under optimal conditions, that is, 2 mol% Ru-1 or RuCl3 in
by Mitsudo, Dixneuf, Bruneau and others52–59. The aminolysis of dioxane at 80 °C, the amide forms in near quantitative yield
enol esters takes place under similarly mild conditions60–63. within 6 h with acetylene as the carboxylate activator
However, for all known catalysts, the two reaction steps are (Table 1, entry 9, Supplementary Table 1). Higher alkynes are
incompatible. As a result, this technology appeared limited to inactive as activators, but with ethoxyacetylene and Ru-1 as

a c
OH
O Δ –H2
Lewis acid Ru-cat. R1
R1 OH or B(OR)3
+ (cat.)
R2 O R2 O d
H2 N H2N DTBP
R2
R1 N Cu/Ag-cat. R1
b H
OH e
R1 Δ H2O2
+ R1'
Ru-cat. Mn-cat.
N R2'

Figure 1 | Atom-efficient approaches to amide bond formation. (a) Thermal or Lewis acid-mediated dehydration of ammonium carboxylates. (b) Catalytic
addition of alcohols to nitriles. (c) Dehydrogenative coupling of alcohols with amines. (d) Oxidative coupling of aldehydes and amines. (e) Oxidative
coupling of alkynes and amines.

2 NATURE COMMUNICATIONS | 7:11732 | DOI: 10.1038/ncomms11732 | www.nature.com/naturecommunications

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11732 ARTICLE

Table 1 | One-pot activation and amidation of carboxylic acids with acetylene*.

Cl Ru Cl
O 2a O Cl Ru Cl
+
[Ru]
Ph O– H3N Ph Ph N Ph Ru
Solvent H
Cl Cl
6aa 5aa
Ru-1 Ru-2

Entry Solvent [Ru] (mol%) Yield (%)

1 1,4-dioxane RuCl33H2O (1) 75
2 1,4-dioxane Ru-2 (0.5) 73
3 1,4-dioxane Ru-1 (1) 81
4 Ethyl acetate Ru-1 (1) 66
5 Toluene Ru-1 (1) 64
6 Tetrahydrofuran Ru-1 (1) 62
7 Acetonitrile Ru-1 (1) 25
8 Water Ru-1 (1) 0
9 1,4-dioxane Ru-1 (2) 94 (93)
10 1,4-dioxane Ru-1 (3) 84
11 1,4-dioxane Ru-1 (5) 71
12w 1,4-dioxane – 0
13z 1,4-dioxane Ru-1 (2) 87
14y 1,4-dioxane Ru-1 (2) 1
15z,|| NMP Ru-1 (1.5) 99 (99)
NMP, N-methyl-2-pyrrolidone; Ru-1, dichloro[(2,6,10-dodecatriene)-1,12-diyl]ruthenium.
*Reaction conditions: 0.5 mmol 6aa, 0.25 mmol 4a, 1.7 bar acetylene, Ru-catalyst, 0.5 ml solvent, 80 °C, 6 h. Yields were determined by GC analysis using n-tetradecane as internal standard; isolated
yields in parentheses.
wwithout Ru-catalyst.
z1.5 mmol 2b instead of 2a.
y1.5 mmol 1-hexyne instead of 2a.
||1 ml solvent, 40 °C, 4 h.

Table 2 | Scope of the amidation with acetylene as the activating agent*.

2a O
O
+ R3 Ru-1 R3
H2N R1 N
R1 O 1,4-dioxane
R2 80 °C, 6 h R2
6 5
O
Alkyl O O O
Ph N
H N Ph N Ph N Ph
Alkyl = benzyl: 5aa, 93% H H H
cyclohexyl: 5ab, 10% S
MeO
ethyl: 5ac, 34%
n-butyl: 5ad, 27% 5ca, 89% 5da, 44% 5ba, 75%

*Reaction conditions: 1.0 mmol 6, 0.5 mmol 4, 1.7 bar acetylene, 2 mol% Ru-1, 1 ml 1,4-dioxane, 80 °C, 6 h. Isolated yields.

catalyst, full conversion was observed already at 40 °C within 4 h Applicability of the developed processes. The scope of the
(entries 13  15). Under identical conditions, RuCl3 gives only ecologically and economically beneficial acetylene protocol is
unsatisfactory yields for this activator (Supplementary Table 2). illustrated in Table 2. Aliphatic, aromatic and heteroaromatic
The advantages of the somewhat less atom-economic carboxylates were successfully coupled with primary amines.
ethoxyacetylene are that it is more easily handled on small scales Unfortunately, the substrate scope of this protocol is limited by
than gaseous acetylene, and that inert ethyl acetate rather than the solubility of the alkylammonium carboxylates in dioxane, the
acetaldehyde is released. optimal solvent for acetylene gas.
Both new protocols were compared with two-step procedures Such restrictions do not apply to the ethoxyacetylene protocol
using established catalysts64, in which the enol esters are in the solvent N-methyl-2-pyrrolidone, which is applicable to a
formed in a separate step, with consecutive addition of the remarkably wide range of substrates (Table 3). Aromatic,
amine either in the same solvent or after solvent exchange. With heteroaromatic and aliphatic carboxylic acids reacted with
acetylene as the activator, no conversion could be achieved, and benzylamine to give high yields of the corresponding amides.
with ethoxyacetylene, the yields obtained in these two-step Diverse functionalities including halo, ether, amide, aldehyde,
syntheses were much lower than those obtained with our ester and even-free OH groups were tolerated. Other primary
convenient one-step protocols (Supplementary Tables 1 and 2). and secondary amines were successfully converted to the

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ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11732

Table 3 | Scope of the amidation with ethoxyacetylene as activating agent*.

O R3 OEt O
HN R3
+ 2b
R1 OH R2 R1 N
Ru-1
1 4 5 R2

FG=H: 5aa, 99% O Alkyl= cyclohexyl: 5ca, 99%

O
p-OMe: 5ba, 83% i-butyl: 5ea, 99%
Bn Bn
p-NO2: 5ga, 93% Alkyl N t-butyl: 5fa, 50%
N H
H p-Cl: 5ha, 96% (CH2)3Ph: 5ua, 99%
p-CN: 5ia, 81%
FG o-OMe: 5ja, 92%
m-OMe: 5ka, 99% O R = H: 5ag, 92%†
m-NMe2: 5la, 87% R cyclohexyl: 5ab, 87%†
p-Br: 5ma, 93% Ph N ethyl: 5ac, 87%†
H n-butyl: 5ad, 78%†
p-COOMe: 5na, 81%
t-butyl: 5ah, 41%†
p-CHO: 5oa, 99%
p-CF3: 5pa, 88%
O
O O O O
Bn
N Bn Bn Ph
H N A N
H Ph N
X 4 H H
N
X = S: 5da, 99% 5sa, 50% 5qa, 98% 5af, 18%†
X = O: 5wa, 99%

O OH O O
O O H
Bn N Bn Ph Bn
N Bn Bn N N
EtO N H H
H H
Ph O OH OH
5va, 74% 5ra, 44% 5ya, 82% 5aaa, 99%
O O
O
Bn H O
N N Bn Ph N
7 H Bn N
H X Ph NEt2
O OH
4
5xa, 99% 5aba, 61%§ X = CH2: 5ai, 92%† 5ae, 35%†
O: 5aj, 70%†

O O Ph Ph
O Cbz O O
Cbz
O Bn
Ph N N HN OEt N OEt
H N N
H H
O O O
5ak, 13%† 5ta, 79% 5afl, 82%†,‡ 5adl, 81%†,‡

Ph Cbz O
O Cbz O Cbz O
H HN OMe
Ph N Bn HN OEt HN OEt N
N N N H
H H H O
O MeS O O Ph
Ph
5za, 88% 5ael, 99%†,‡ 5aco, 96%†,‡ 5acn, 72%†,‡

Ph OH
Cbz O Cbz O
HN OEt HN OEt
N N
H H
O O
Ph Ph
†,‡ †,‡
5acl, 73% 5acm, 54%

*Reaction conditions: 1.0 mmol 1, 1.5 mmol 4, 1.5 mmol 2b, 1.5 mol% Ru-1, 2 ml NMP, 40 °C, 4 h. Isolated yields.
w80 °C, 6 h.
z2 ml of toluene instead of NMP.
y3 mmol 2b and 4a.

4 NATURE COMMUNICATIONS | 7:11732 | DOI: 10.1038/ncomms11732 | www.nature.com/naturecommunications

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11732 ARTICLE

R2 H2N R3 Methods
O 2 O 4 O For analytical data and preparation methods of the compounds in this article, see
R3 Supplementary Figs 6–111 and Supplementary Methods.
R1 OH Ru-cat. R1 O R2 R1 N
1 3 5 H
[Ru]
H+ O R2 General techniques. All reactions were performed in oven-dried glassware
H+ containing a Teflon-coated stirring bar and dry septum under a nitrogen
R2 atmosphere. For the exclusion of atmospheric oxygen from the reaction media,
solvents were degassed by argon sparge and purified by standard procedures before
O [Ru] O use. Non-aqueous amines were distilled before use. All reactions were monitored
[Ru] by gas chromatography (GC) using n-tetradecane as an internal standard or by
R1 O
R1 O high-performance liquid chromatography using anisole as an internal standard.
R2 Response factors of the products with regard to n-tetradecane/anisole were
2a: R2 = H R2 obtained experimentally by analysing known quantities of the substances. GC
2b: R2 = OEt O [Ru] analyses were carried out using an HP-5 capillary column (Phenyl Methyl Siloxane
30 m  320  0.25, 100/2.3-30-300/3) and a temperature programme beginning
R1 O
with 2 min at 60 °C followed by 30 °C/min ramp to 300 °C, then 3 min at this temp.
High-performance liquid chromatography analyses were carried out using a
Figure 2 | Catalytic amide condensation via enol esters. The proposed
Shimadzu LC-2010A. The stationary phase was a reversed phase column
catalytic cycle starts with the coordination of a carboxylate and an alkyne to LiChroCart PAH C-18 from Merck KGaA with acetonitrile and water as eluents
the ruthenium catalyst, followed by an addition of the carboxylate to the at 60 °C and the following solvent programme: starting from 10 vol% acetonitrile
alkyne. After protonolysis, the enol ester intermediate is released, which for 1 min, followed by increasing acetonitrile to 70 vol% during 23 min, then
then acts as an acylating agent for the amine, yielding the desired amide decreasing again to 10 vol% rapidly and maintaining this value for the next
2 min. Column chromatography was performed using a Combi Flash
along with the carbonyl-byproduct. Companion-Chromatography-System (Isco-Systems) and RediSep packed columns
(12 g). nuclear magnetic resonance spectra were obtained on Bruker AMX 400 or
corresponding benzamides in good to excellent yields when on Bruker Avance 600 systems using DMSO-d6, Chloroform-d3 or Toluene-d8 as
solvent, with proton and carbon resonances at 400/600 MHz and 101/151 MHz,
increasing the temperature to 80 °C to ensure full conversion respectively. Mass spectral data were acquired on a GC-MS Saturn 2,100 T
(Supplementary Table 3). Remarkably, the coupling of less (Varian). Infrared spectra were recorded on Perkin Elmer Spectrum 100 FT-IR
nucleophilic compounds such as amides, aniline and Spectrometer with Universal ATR Sampling Accessory. Melting points are
diethylamine with benzoic acid also gave the desired products, uncorrected and were measured on a Mettler FP 61. ESI MS data were acquired on
a Bruker Esquire 6,000 and evaluated with mMass software. Sample solutions at
albeit in low yields. Other oxygen- or sulfur-based nucleophiles concentrations of B1  10  4 M were continuously infused into the ESI chamber
could not be converted. at a flow rate of 2 ml min  1 using a syringe pump. We use nitrogen as drying gas at
The synthetic concept may also be used for peptide couplings. a flow rate of 3.0–4.0 l min  1 at 300 °C and spray the solutions at a nebulizer
Various N-protected amino acids were successfully coupled with pressure of 4 psi with the electrospray needle held at 4.5 kV. CHN-elemental
amino acid esters. Without additives, racemization could not fully analyses were performed with a Hanau Elemental Analyzer vario Micro cube and
HRMS with a Waters GCT Premier.
be suppressed but remained below 10%, which is a good basis for
dedicated optimization.
Synthesis of amides using acetylene as activator. An oven-dried headspace vial
with Teflon-coated stirring bar was charged with the corresponding ammonium
Mechanistic considerations. The reaction mechanism was carboxylate (1 mmol) and dichloro[(2,6,10-dodecatriene)-1,12-diyl]ruthenium
(5.06 mg, 20 mmol). The atmosphere was changed three times with nitrogen, then
investigated by in situ nuclear magnetic resonance spectroscopy. N-methylpyrrolidone (1 ml) and the corresponding amine (0.5 mmol) were added.
The experiments confirmed the intermediacy of enol esters, The vial was placed in an autoclave reactor, the atmosphere was changed twice with
which formed within minutes and were consumed in the course acetylene, and a pressure of 1.7 bar was set. The mixture was then heated to 80 °C
of the reaction (see Supplementary Table 6 and Supplementary for 6 h. After cooling down to room temperature, the mixture was diluted with
Fig. 1 respectively). We thus conclude that as outlined in Fig. 2, 20 ml of ethyl acetate and washed with each 20 ml of saturated NaHCO3 solution,
water and brine. The organic layer was dried with MgSO4, the solvent removed
the reaction proceeds via a Ru-catalysed hydroacyloxylation under reduced pressure and the residue purified by column chromatography
via a standard catalytic cycle67,71 followed by aminolysis. (SiOH, ethyl acetate/cyclohexane gradient).
In ESI MS investigations of the reaction mixture, species with
m/z values of 754 and 647 were dominant. These were
Synthesis of amides using ethoxyacetylene as activator. An oven-dried
identified as [RuCl2(benzyl amine)3(ethoxyacetylene)2 headspace vial with Teflon-coated stirring bar was charged with the corresponding
(benzoate)] þ and [RuCl2(benzyl amine)2(ethoxyacetylene)2 carboxylic acid (1 mmol) and dichloro[(2,6,10-dodecatriene)-1,12-diyl]ruthenium
(benzoate)] þ . In tandem mass spectrometry (MS) experiments, (5.06 mg, 15.0 mmol). The atmosphere was changed three times with
these adducts fragmented with loss of benzyl amine ligands nitrogen, then N-methylpyrrolidone (2 ml), benzyl amine (164 mg, 167 ml,
1.5 mmol) and ethoxyacetylene (40 wt%-solution in hexane; 210 mg, 299 ml and
and formation of the six-coordinate [RuCl2(benzyl amine)1 1.5 mmol) were added in this order. The mixture was then heated to 40 °C for 4 h.
(ethoxyacetylene)2(benzoate)] þ complex, which we believe to After cooling down to room temperature, the mixture was diluted with 20 ml of
be the catalyst resting state. It is reasonable to assume that it is a ethyl acetate and washed with each 20 ml of sat. NaHCO3 solution, water and
Ru(IV)-complex, since it bears three anions and is still positively brine. The organic layer was dried with MgSO4, the solvent removed under reduced
pressure and the residue purified by column chromatography (SiOH, ethyl acetate/
charged. These investigations suggest the intermediacy of cyclohexane gradient).
high-valent Ru-species, which explains why RuIV pecursors
have a higher activity than the RuII and Ru0 precursors
employed in other catalytic additions. For the details of the Data availability. The authors declare that the data supporting the findings of this
study are available within the article and its supplementary information files.
spectroscopic investigation, see Supplementary Figs 2–5.
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NATURE COMMUNICATIONS | DOI: 10.1038/ncomms11732 ARTICLE

63. Bruneau, C. & Dixneuf, P. H. Selective transformations of alkynes with Acknowledgements

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