One-pot mechanosynthesis of aromatic amides and dipeptides from carboxylic acids and amines

Article abstract of DOI:10.1039/c2cc36613d

Environmentally friendly one-pot synthesis of amides, bis-amides and dipeptides by mechanochemical carbodiimide-mediated coupling of carboxylic acids and amines is described; high reaction yields and simple aqueous work-up allow for the clean, practical and fast preparation of a variety of compounds containing the amide bond from readily accessible reagents.

Full text of DOI:10.1039/c2cc36613d

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Cite this: Chem. Commun., 2012, 48, 12100–12102
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COMMUNICATION
One-pot mechanosynthesis of aromatic amides and dipeptides from
carboxylic acids and amineswz
Vjekoslav Strukil,* Boris Bartolec, Tomislav Portada, Ivica Ðilovic, Ivan Halasz and
a
a
a
b
c
ˇ
´
a
´
Davor Margetic*
Received 11th September 2012, Accepted 29th October 2012
DOI: 10.1039/c2cc36613d
Environmentally friendly one-pot synthesis of amides, bis-amides
and dipeptides by mechanochemical carbodiimide-mediated coupling
of carboxylic acids and amines is described; high reaction yields and
simple aqueous work-up allow for the clean, practical and fast
preparation of a variety of compounds containing the amide
bond from readily accessible reagents.
have used ball-milling of activated urethanes with amino acids
to construct peptide derivatives in high yields.
In search of a procedure that would allow the amide mechano-
synthesis without the need for pre-activated reagents, excess
reagents or bulk solvents in the purification step,10–12 we focused
on further extension of the established benefits of milling
mechanochemistry.8 We now demonstrate that such a procedure,
complementary to the existing mechanochemical methods, is
accessible by ball-milling of commercially available amines and
carboxylic acids or amino acids in one-pot mode. This enables
the synthesis of aromatic achiral and chiral amides as well
as dipeptides in excellent isolated yields in a simple and
environmentally-friendly fashion. The key features of our approach
are mechanochemical in situ activation of the carboxylic acid
by N-ethyl-N0-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDCꢀHCl) and simple aqueous work-up of the reaction
mixture which affords the amide products in high purity.
Amide functionality is one of the fundamental structural
motifs in (bio)organic molecules such as peptides and proteins.1
Many pharmaceutically active, naturally occurring (e.g. b-lactams)2
and synthetic compounds (e.g. anaesthetic lidocaine)3 possess
the amide group as the basis of their biological effectiveness.
Its geometric and electronic properties together with hydrogen-
bonding ability render these compounds as useful materials,
e.g. nylon polymers and Kevlar composites, whose bulk
properties are greatly determined by the nature of the amide
functionality.4 The directionality of hydrogen bond donor and
acceptor sites within the amide group allows for a rational
design of materials by applying the principles of crystal
engineering.5 New chiral organocatalysts based on the amide
group have been developed for direct asymmetric aldol con-
densations, Strecker and Morita–Baylis–Hillman reactions
and allylic alkylations.6
The mechanochemical screening of the typical coupling
reagents13 was performed by neat grinding (NG) using two
8 mm grinding balls (Scheme 1a). As a model reaction, we
selected the condensation of benzoic acid (Ar = Ph) with
p-anisidine (R = OCH3) which yields N-(4-methoxyphenyl)-
benzamide (1a) (Scheme 1b and Table S1, ESIz). 1H NMR
analysis showed that N,N0-dicyclohexyl- (DCC) and N,N0-
diisopropylcarbodiimide (DIC) gave similar results with the
conversion of 87–88% after 30 minutes. EDCꢀHCl-mediated
coupling resulted in slightly lower conversion (83%), whereas
carbonyl diimidazole (CDI) failed to produce amide 1a in an
isolable quantity. As the beneficial effect of changing the size
While numerous reports for amide synthesis exist,7 very few
focus on solid-state grinding8 as a means to access this class of
compounds. Thakuria and Das have described the synthesis of
quinoxalines by grinding the reactants using a mortar and
pestle9 whereas Vyle et al. have reported amide synthesis by
mechanochemical milling of activated N-hydroxysuccinimidyl
esters with amines.10 Hernandez and Juaristi11 and Lamaty et al.12
´
a
´
Division of Organic Chemistry and Biochemistry, Ru:er Bosˇkovic
Institute, Bijenicˇka cesta 54, HR-10002 Zagreb, Croatia.
E-mail: vstrukil@irb.hr, margetid@irb.hr
b Department of Chemistry, Faculty of Science, University of Zagreb,
Horvatovac 102A Zagreb, Croatia
c
´
Division of Chemistry of Materials, Ru:er Bosˇkovic Institute,
Bijenicˇka cesta 54, HR-10002 Zagreb, Croatia
w This article is part of the ChemComm ‘Mechanochemistry: funda-
mentals and applications in synthesis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all compounds and crystallo-
graphic data for 1e, 2d, 2e, 4 and 6a. CCDC 900474–900476. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc36613d
Scheme 1 (a) Structures of the coupling reagents tested; (b) synthesis
of N-aryl amides 1–3 under mechanochemical conditions in a ball mill;
(c) one-pot mechanosynthesis of dipeptides 10a–e in a ball-mill.
c
12100 Chem. Commun., 2012, 48, 12100–12102
This journal is The Royal Society of Chemistry 2012

and number of balls on the chemical reactivity has been pre-
viously established,14 the same set of experiments was repeated
with a single grinding ball of 12 mm diameter. A substantial
increase in the conversion was achieved with EDCꢀHCl as the
coupling reagent, which almost quantitatively (>97%) trans-
formed reactants into the desired amide 1a in only 10 minutes
(Fig. S1, ESIz). We found EDCꢀHCl especially suitable as a
green chemistry reagent, as it allows the isolation procedure to be
carried out in the absence of harmful organic solvents.
Table 2 Scope of the EDCꢀHCl-mediated mechanochemical coupling
of (amino)acids with aliphatic and aromatic amines
Product
Acid
Amine
Conditionsa
Yieldb/%
4
5
6a
6b
Succinic
Fumaric
Benzoic
Benzoic
Anilinec
NG, 10 min 77
LAG, 30 min 79
LAG, 10 min 93d
p-Anisidinec
Morpholine
Thiomorpholine LAG, 10 min 92d
(1R,2R)-7 Benzoice
LAG, 30 min 98
The 3-dimethylaminopropyl urea by-product is water-soluble13
and, assuming poor water-solubility of N-aryl amides,15 a simple
aqueous work-up and filtration should suffice to provide the pure
amide products in a clean and environmentally benign way. With
the optimized conditions in hand, the syntheses of a series of
N-aryl benzamides 1a–e were conducted. The liquid-assisted
grinding (LAG)16 approach worked well with all substrates.
After 10 minutes, the crude mixture was suspended in water and
upon stirring for 15 minutes the precipitated product was simply
filtered off and dried in air to afford pure amide (Table 1).
By applying the same reaction conditions, analogous sets of
N-aryl-1-naphthamides 2a–e and N-aryl-2-naphthamides 3a–e
were prepared. While the isolated yields in 1-naphthamide
series 2a–e were lower even after 30 minutes of LAG (although
still better than in NG experiments, Fig. S3, ESIz), 2-naphthamide
derivatives 3a–e were isolated in an excellent >94% yield in just
10 minutes. This observation could be explained by steric effects
imposed by a fused benzene ring of the 1-naphthyl framework.
Considering the complexity and the number of different reac-
tion pathways in amide bond-forming reactions,13 we note a
remarkable chemoselectivity and straightforward reactivity in
this mechanochemical multicomponent one-pot reaction.
The scope of the reaction was investigated with aliphatic
and aromatic acids and amines (Table 2). Succinic and fumaric
acids were used for the synthesis of the corresponding bis-
amides 4 and 5. Aliphatic secondary amines morpholine and
thiomorpholine provided tertiary N-benzoylated amides 6a
and 6b in high yields after 10 minutes of grinding. Besides
achiral reagents, we also studied EDCꢀHCl-coupling using
(1R,2R)-8 Benzoice
LAG, 30 min 88
9a
9b
Boc-Ala-OH p-Anisidine LAG, 30 min 87
Boc-Ala-OH 4-Chloroaniline LAG, 30 min 88
a
12 mm diameter stainless steel grinding ball, 30 Hz frequency, LAG
b
with nitromethane, Z = 0.25 mL mgꢁ1
of amine. Purified by column chromatography. 2 equivalents of
benzoic acid.
.
c
Isolated yield. 2 equivalents
d
e
chiral (1R,2R)-cyclohexyl- and (1R,2R)-1,2-diphenylethylene-
diamines. The chiral bis-amides (1R,2R)-7 and (1R,2R)-8 were
obtained in excellent yields, suggesting that the milling method-
ology is applicable for the preparation of amide-based chiral
ligands.6
When commercially available N-Boc-protected L-alanine
was coupled with p-anisidine or 4-chloroaniline, the targeted
anilides 9a and 9b were isolated in high yield. This result
prompted us to explore one-pot milling for the synthesis of
simple N- and C-termini protected dipeptides based on glycine
and alanine (Scheme 1c). Having optimised the reaction condi-
tions for Boc-L-Ala-Gly-OBn dipeptide 10c,17 we conducted
the EDCꢀHCl-mediated mechanosynthesis of other homo- and
heterodipeptides 10a–e starting from N-Boc-protected glycine
or alanine, benzyl esters of glycine and alanine in the form of
tosylate salts and DMAP as the base (Table 3).
Whereas glycine-derived homodipeptide 10a was obtained
in moderate 70% yield, L-alanine homodipeptide 10b was
isolated in better yield of 80%. Its diastereomer Boc-D-Ala-
L-Ala-OBn 10e, as well as Boc-D-Ala-Gly-OBn 10d which is
the enantiomer of 10c, were also successfully prepared. We
did not notice racemisation under applied conditions,12
which is the usual drawback of conventional solution-based
procedures.18 The established catalytic activity of dipeptides
under grinding conditions19 could therefore be coupled with
Table 1 Reaction conditions and yields for the mechanosynthesis of
N-aryl amides 1–3 via EDCꢀHCl-mediated coupling
Product
Ar
R
Conditionsa
Yieldb/%
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
Ph
Ph
Ph
Ph
OCH3
CH3
H
F
Cl
OCH3
CH3
H
F
Cl
OCH3
CH3
H
F
Cl
LAG, 10 min
LAG, 10 min
LAG, 10 min
LAG, 10 min
LAG, 10 min
LAG, 30 min
LAG, 30 min
LAG, 30 min
LAG, 30 min
LAG, 30 min
LAG, 10 min
LAG, 10 min
LAG, 10 min
LAG, 10 min
LAG, 10 min
95
97
92
95
99
88
87
Table 3 EDCꢀHCl-mediated mechanosynthesis of dipeptides 10a–ea
Ph
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
Product aa1/aa2
R1 R2 R3 R4 Yieldb/%
85
10a
10b
10c
10d
10e
Boc-Gly-OH/Gly-OBnc
H
H
H
H
CH3
CH3
H
H
H
H
H
H 70
CH3 80
80/85c
80/79c
96
Boc-L-Ala-OH/L-Ala-OBnc CH3
Boc-L-Ala-OH/Gly-OBnc
Boc-D-Ala-OH/Gly-OBnc
Boc-D-Ala-OH/L-Ala-OBnc
CH3
H
H
H
H
78
79
96
96
94
95
CH3 81
a
A single 12 mm diameter stainless steel ball, 180 minutes, 30 Hz
frequency, LAG with nitromethane, Z = 0.25 mL mgꢁ1, 2 equivalents
of DMAP as the base to deprotonate the unprotected amino acid and
as the activator of EDCꢀHCl and 20 equivalents of NaCl as the
a
A single 12 mm diameter stainless steel ball, frequency of 30 Hz,
anhydrous nitromethane as the grinding liquid (Z = 0.25 mL mgꢁ1);
Isolated yield after aqueous work-up; Yield after purification of the
crude mixture by column chromatography.
b
c
b
c
grinding auxiliary. Isolated yield after aqueous work-up. aa2 were
used in the form of tosylate salts.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 12100–12102 12101

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Fig. 1 (a) Measured and simulated PXRD patterns of diamide 4;
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parallel chains are stacked by C–Hꢀ ꢀ ꢀp interactions into a 2-D
network (Fig. 1b, S53 and S54, ESIz).
15 The room temperature solubility of the isolated amides in water
was estimated to be less than 0.2 mg mLꢁ1
.
The purity of synthesised amides (see ESIz) enabled structure
determination from PXRD data21 collected on a laboratory
diffractometer, in line with the requirements of a solvent-free
research laboratory.14,16 In the crystal, 1e molecules are con-
nected by linear hydrogen bonds into 1-D tapes (Fig. S44,
ESIz). Molecules of 6a are held together by weak C–Hꢀ ꢀ ꢀO
and CAr–Hꢀ ꢀ ꢀH–CAr interactions (Fig. 1c–e).
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´ ´ ´
´
,
´
´
17 Short neat grinding with NaHCO3 or K2CO3 as the base and the
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18 M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag,
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J. G. Herna
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´
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In summary, we demonstrated a mechanochemical methodology
for the efficient synthesis of amides and dipeptides from com-
mercially available acids and amines. In situ EDCꢀHCl-mediated
coupling obviates the need to pre-activate reactants and allows
the amide product isolation using only water. This reactivity
demonstrates how the course and design of mechanosynthesis
can be augmented by stoichiometric or catalytic auxiliaries.22
We acknowledge the financial support of the Ministry of
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0982933-2920, 098-0982933-3218 and 098-0982904-2912) and
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9, 3133Crystal structures of 1e and 6a were solved using TOPAS
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´
,
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Dr Ernest Mestrovic
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c
12102 Chem. Commun., 2012, 48, 12100–12102
This journal is The Royal Society of Chemistry 2012