Mechanochemical Synthesis of Dipeptides Using Mg-Al Hydrotalcite as Activating Agent under Solvent-Free Reaction Conditions

Article abstract of DOI:10.1002/ejoc.201601276

Given the high demand for green and sustainable synthetic methods for the formation of amides and peptidic bonds, herein we report the efficient, solvent-free mechanochemical synthesis of dipeptides from N-protected amino acids and amino acid methyl ester

Full text of DOI:10.1002/ejoc.201601276

A Journal of
Accepted Article
Title: Mechanochemical synthesis of dipeptides using Mg-Al
hydrotalcite as activating agent under solvent-free reaction
conditions
Authors: José M. Landeros and Eusebio Juaristi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601276
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Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
Mechanochemical synthesis of dipeptides using Mg-Al
hydrotalcite as activating agent under solvent-free reaction
conditions
[
a]
[a,b]
José M. Landeros, and Eusebio Juaristi*
Dedication ((optional))
Abstract: Given the high demand for green and sustainable
synthetic methods for the formation of amides and peptidic bonds,
herein we report the efficient, solvent-free mechanochemical
synthesis of dipeptides from N-protected amino acids and amino
acid methyl ester hydrochlorides in the presence of 1-hydroxy
benzotriazole (HOBt) and N-ethyl-N′-(3-dimethylaminopropyl)
carbodiimide hydrochloride (EDC) as coupling reagents, and using
Mg-Al hydrotalcite-like minerals as green activating agent. From
commercial Mg-Al hydrotalcite (HT-S) we obtained its calcined (HT-
C) and reconstructed (HT-R) modifications, which were evaluated as
activating heterogeneous bases in amidation reactions, replacing
2 2
potentially hazardous organic solvents such as CH Cl and DMF,
toxic catalysts such as tertiary amines, harsh reaction conditions,
long reaction times, and concomitant formation of large
quantities of chemical waste. These facts are contrary to the
[5]
principles of sustainable chemistry,
which mandate the
minimization or even complete removal of solvents in chemical
transformations, the use of efficient catalysts, as well as the
development of energy-saving processes.
In this regard, in recent years several green strategies in
organic chemistry that employ non-traditional energy sources,
such as ultrasound irradiation, microwave, and high-speed ball-
[
6]
commonly used toxic and/or corrosive bases (e.g., NEt
3 2
, iPr NEt and
milling (HSBM) have been developed. The latter technique
(HSBM) also known as mechanochemistry, has proven to be a
viable green alternative for the synthesis of amides and peptides
under solvent-free conditions or liquid assisted grinding (LAG),
achieving good yields at short reaction times, reducing
NaOH). As a practical application of this strategy, various α,α- and
α,β-dipeptides were prepared in good to excellent yields. Under
optimized reaction conditions (vibrating mill at 25 Hz for 75 min) HT-
S and HT-R showed higher activity (89% yield of the desired
peptide) as compared with HT-C (57% yield). The present protocol
offers several advantages, including the use of readily available
reagents and inexpensive materials, easy work-up, simple recovery
and recyclability of the hydrotalcite activator, and short reaction
times.
[
7]
production costs, and minimizing waste of valuable chemicals.
In this context, the development of catalytic protocols and
the use of heterogeneous activators is highly desirable in the
quest of sustainable chemistry. In this regard, the replacement
of homogeneous catalysts/activating agents by heterogeneous
counterparts offers several advantages such as easy separation
and recovery of the catalyst/activating agent from the reaction
medium, no need for neutralization and extraction steps,
possibility of recycling of the catalyst/activating agent, and
Introduction
[
8]
reduction of waste formation.
The formation of the peptidic (amide) bond is the key step
in peptide and protein synthesis, and the relevance of this
Among heterogeneous solid bases, hydrotalcite minerals
HT´s) have been used as replacement of classic bases (alkali
(
[
1]
synthetic process is recognized both in industry and academia.
The amide functional group is present in about 25% of all drugs
metal hydroxides or amines) in large-scale synthesis of fine
chemicals and in pharmaceutical processes. HT´s are
commercially available, inexpensive synthetic or natural anionic
clays. Naturally occurring HT has the general formula
[
2]
currently commercialized, and this fact has motivated many
recent advances in the area of synthesis of amides and peptides,
including the development of new, racemization-suppressing
2+
3+
x+
n−
2+
3+
[
Mg 1−xAl
x
(OH)
2
] (CO
3
)
2
x/n·mH O, where Mg and Al are di-
[
3]
coupling agents, as well as methods for the direct activation of
n−
and trivalent cations, respectively, (CO
compensating anion, x corresponds to the fraction of trivalent
cations in the brucite-type layers [Mg(OH) ] and m is the water of
Numerous studies of the preparation and
determination of the physicochemical properties of HT´s have
3
)x/n is an interlayer
[
3b,4]
carboxylic acids for their condensation reaction with amines.
Nevertheless, most synthetic methods for amide bond formation
are performed in homogeneous phase, requiring the use of
2
[9]
crystallization.
[
10]
been reported. Among the three most important properties of
HT´s are: (1) its composition, which gives rise to a solid material
with basic character, modulated by the corresponding anion. (2)
The formation of homogeneous mixed oxides after heat
treatment (420-470 °C) with generation of MgO acid-base pairs.
[
[
a]
b]
J. M. Landeros, E. Juaristi
Departamento de Química
Centro de Investigación y de Estudios Avanzados,
Instituto Politécnico Nacional,
Avenida IPN No. 2508, 07360 Ciudad de México, Mexico
E-mail: juaristi@relaq.mx, ejuarist@cinvestav.mx
http://www.relaq.mx/RLQ/EusebioJuaristi.html
E. Juaristi
(
3) When calcined hydrotalcite is rehydrated under a flow of
water vapor at ambient temperature, the original layered
structure is restored, in a so-called “memory effect”. These
characteristics turn HT’s into interesting materials for application
El Colegio Nacional
Luis González Obregón No. 23, Centro Histórico,
06020 Ciudad de México, Mexico.
[9,11]
as heterogeneous activating agents.
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
Recently Morales-Serna and coworkers reported the
synthesis of peptides and amides under activation by
hydrotalcite, in the presence of EDC and HOBt, and under
[
12]
heterogeneous conditions using CH
the observed yields varied from good to excellent, extended
reaction times and use of CH Cl as reaction medium demerit its
application as a synthetic green chemistry strategy. On the other
hand, Štrukil and coworkers have reported the
2 2
Cl as solvent. Although
2
2
mechanochemical synthesis of amides and dipeptides by
carbodiimide-mediated coupling. Among several coupling agents,
EDC turned out most suitable under neat or LAG conditions.
Afterwards, Lamaty and coworkers were able to synthesize di-,
tri- and tetra-peptides in good yields, using EDC as coupling
agent and in the presence of Oxyme (ethyl hydroxy-
iminocyanoacetate), NaH
2 4
PO and LAG conditions.
Taking these developments into account, we decided to
Figure 1. Powder XRD patterns of commercial hydrotalcite (HT-S),
hydrotalcite calcined to 450 °C (HT-C) and reconstructed hydrotalcite (HT-R).
[
12]
adapt the protocol suggested by Morales-Serna et al. to carry
out peptide synthesis in a green mechanochemical strategy.
Thus, we report here the mechanosynthesis of ,-, ,- and

,-dipeptides by amidation between N-protected-amino acids
FTIR-ATR spectra of commercial (HT-S), calcined (HT-C)
and reconstructed hydrotalcite (HT-R) are shown in Figure 2.
The spectrum of HT-S reveals a broad band at 3413 cm ,
characteristic of hydroxyl group stretching vibration, which is
attributed to interlayer water and hydroxyl groups of the brucite-
like layers. Hydrogen bonding between carbonate ions and
water in the interlayer is detected as a shoulder close to 3027
and amino methyl ester hydrochlorides activated catalyzed by
hydrotalcite-like minerals in the presence of appropriate coupling
reagents and under solvent-free conditions.
-1
The present work is part of our efforts to extend the
[
13]
applicability of mechanochemistry in organic synthesis.
-
1
-1
cm , whereas the bands at 1640 and 1365 cm are associated
with interlayer water molecules and carbonate anions,
Results and Discussion
[
15]
-1
respectively. The bands at 929 and 771 cm are assigned to
Al–O bonds.
On the other hand, the bands 3413 and 1365 cm , related
to water bending vibrations and interaction of water–carbonate
ions in the interlayer, are no longer present in the sample of HT-
C, due to loss of water and carbonate ions during calcinations.
[
16]
2
.1. Characterization of hydrotalcite minerals
Powder XRD patterns of commercial Mg–Al hydrotalcite
HT-S), its calcined form (HT-C), and reconstructed form (HT-R)
−
1
(
are shown in Figure 1. The HT-S sample display sharp and
intense reflections at 11.6°, 23.3°, 60.7° and 62.0° [ascribed to
diffraction by planes (0 0 3), (0 0 6), (1 1 0), and (1 1 3),
-1
The weak band at 1400 cm is attributed to interaction between
remaining CO
2
2+
3
and Mg .
respectively] characteristic of
hydrotalcite (JCPDS: 41-1428). The calcined hydrotalcite (HT-C,
50 °C) exhibit low reflections at 43.4°and 63.0° [ascribed to the
a
well-crystallized Mg–Al
Rehydration of HT–C in a decarbonated–water saturated
gas flow induced a reconstruction of hydrotalcite structure. The
HT-R exhibits bands attributed to hydroxyl groups and water
4
diffraction (4 0 0), and (4 4 0) planes, respectively] associated
with Mg(Al)O mixed oxide periclase-like structure, similar to XRD
of MgO (JCPDS: 45-0946), owing to loss of interlayer water and
decarbonation in a lamellar structure. Rehydration of HT-C in
water vapor restored the layered structure as result of the
memory effect. HT-R shows similar reflection pattern relative to
HT-S; however, HT-R is less crystalline as reflected by intensity
and sharpness of (0 0 3) and (0 0 6) planes, which are directly
-1
around 3448 and 1640 cm , respectively. Finally, the band at
-1
[10c]
1
369 cm corresponds to carbonate ions.
[
14]
correlated to the crystallinity of the material.
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European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
Table 1. Optimization of the Reaction Conditions for the Synthesis of N-Boc-L-
[
a]
Leu-L-Ala-OMe Dipeptidic Derivative 3a
.
Time
[min]
Cycles)
HT-S
mg]
Power
[Hz]
No. balls
(d [mm])
Reactor
Type
[c]
Entry
[b]
Yield %
[
(
1
2
3
4
4
5
6
7
8
9
62.5
62.5
62.5
62.5
62.5
62.5
62.5
62.5
125
200
250
300
500
250
250
250
250
250
250
250
250
250
--
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (3)
90 (2)
90 (1)
75 (1)
60 (1)
45 (1)
30 (1)
75 (1)
60 (1)
75 (1)
15
20
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
2 (5)
2 (5)
2 (6)
2 (6)
2 (6)
1 (6)
1 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
2 (9)
1 (9)
1 (9)
1 (9)
Jar-1
Jar-1
Jar-1
Jar-2
Jar-2
Jar-2
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
Jar-3
22
35
41
43
43
38
63
65
83
88
89
87
45
89
89
89
89
82
81
50
89
83
traces
Figure 2. Infrared spectra of hydrotalcite-like materials.
2.2. Mechanosynthesis of dipeptides catalyzed by hydrotalcite-
like minerals
10
In order to evaluate the activating potential of the
hydrotalcite-like materials (HT-S, HT-C and HT-R) in amidation
reactions under high speed ball milling (HSBM) and solvent-free
conditions, we began this study following the best experimental
11
12
13
14
15
16
[
12]
conditions described by Morales-Serna et al.,
that is
employing N-Boc-L-leucine (1a, 0.25 mmol), L-alanine methyl
ester hydrochloride (2a, 0.25 mmol), EDC (0.275 mmol), and
HOBt (275 mmol). The parameters examined to optimize this
procedure include the vibration frequency of ball milling (Hz); the
type of material and size of the jar mill, the molar ratio of
hydrotalcyte (HT-S), and the reaction time (Table 1).
17
18
19
20
The vibration frequency effect at 15, 20 and 25 Hz was
examined in an agate jar mill (Jar-1) as shown in entries 1 to 3
21
(
Table 1). Following a sequence of three cycles (90 min each),
22
the highest yield (41%) was obtained at 25 Hz. Subsequently,
the size and type of material of the jar mill were evaluated (Table
[a] Experimental conditions: N-Boc-Leucine 1a (0.25 mmol), L-alanine methyl
ester hydrochloride 2a (0.25 mmol), EDC (0.275 mmol), HOBt (0.275 mmol).
1
, entries 4-7), finding that the stainless-steel Jar-3 (12 mL, 2.1
cm of diameter) at 25 Hz affords product 3a in higher yield
65%). After selecting the operating frequency (25 Hz) and the
[
2
b] Reactor type: Jar-1 of agate (5 mL, 1.2 cm diameter) and ball of agate; Jar-
of stainless steel (6 mL, 1.2 cm diameter) and ball of stainless steel; Jar-3 of
(
stainless steel (12 mL, 2.1 cm diameter). [c] Yield of isolated product (3a) after
type of reactor (Jar-3), the effect of the quantity of HT-S on the
reaction was examined (Table 1, entries 8-12). Best results were
observed when employing 250 mg (0.41 mmol) of HT-S, the
reaction afforded the desired product 3a in 89% yield. Finally,
the reaction time and the number of milling balls were optimized.
Best results were found with reactor Jar-3, with one or two balls,
at 25 Hz, 75 min of reaction time, and 250 mg of HT-S (Table 1,
entries 16 and 20).
A control experiment under the optimal reaction conditions
but without HT-S as activating agent, afforded only traces of the
expected product (entry 22 in Table 1). This result indicates that
it neither HOBt nor EDC are sufficient for the condensation
reaction to take place. That is, the presence of the HT-S as
activating base is crucial for the reaction to proceed.
chromatographic purification.
Once established the optimal conditions for amide bond
formation with commercial HT-S as activating agent had been
established, HT-C and HT-R forms were evaluated (Table 2).
The results show that the HT-C mineral form affords product 3a
in moderate yield (55-57%), even with prolonged reaction times
(
Table 2, entries 2 and 3). By contrast, the material HT-R turned
out to be comparable in efficiency to HT-S (Table 2, entries 4
and 5).
Interestingly, other representative bases such as NaHCO
3
,
Cs
2
CO and K CO were evaluated in order to compare them
3
2
3
with the hydrotalcites. The yields obtained with these inorganic
salts were generally lower (Table 2, entries 6-10).
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European Journal of Organic Chemistry
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FULL PAPER
According to the above observations, both the HT-S and
Table 2. Screening of Activating Agents for the Synthesis of N-Boc-L-Leu-L- HT-R materials present higher activity. Nevertheless, the lower
[
a]
Ala-OMe Dipeptidic Derivative 3a
.
cost of HT-S represents an advantage. Accordingly, we
examined the scope of the HT-S promoting amidation reaction.
A variety of amino methyl ester hydrochlorides were coupled
with different N-protected-amino acids [including the protecting
groups tert-butyloxycarbonyl (Boc); benzyloxycarbonyl (Cbz)
and 9-fluorenylmethoxycarbonyl (Fmoc)] to give the
corresponding dipeptide products in the yields summarized in
Table 3.
Time [min]
[b]
Entry
Catalyst
mg
Yield [%]
(Cycles)
1
2
3
4
5
6
7
8
9
HT-S
HT-C
HT-C
HT-R
HT-R
250
250
250
250
250
250
250
34
75 (1)
89
55
57
89
89
76
78
60
67
15
75 (1)
90 (2)
75 (1)
90 (2)
75 (1)
90 (2)
75 (1)
75 (1)
75 (1)
As part of the present study, recycling of the HT-S
activating material was carried out in the synthesis of dipeptide
3b. The HT-S material that had been recovered after filtration,
was dried at 100 °C and reused. This procedure was repeated
up to four cycles (Table 4). The results show a significant
decrease in product yield after each cycle (Table 4, entries 1-4).
Nevertheless, when the recovered material HT-S of the second
cycle was calcined and rehydrated (see the Experimental
Section), the corresponding reconstructed hydrotalcite HT-R
was obtained and characterized (see Figures S4 and S5 in the
Supporting Information), exhibiting total activity recovery (Table
NaHCO
NaHCO
NaHCO
3
3
3
2
Cs CO
3
250
250
10
K
2
CO
3
[
a] Reaction conditions: N-Boc-Leucine 1a (0.25 mmol), L-alanine methyl ester 4, entry 5).
hydrochloride 2a (0.25 mmol), EDC (0.275 mmol), HOBt (0.275 mmol), Jar-3
of stainless steel (12 mL, 2.1 cm diameter). [b] Yield of isolated product (3a)
after chromatographic purification.
[
a]
Table 3. Scope of Dipeptide Synthesis Under Solvent-Free Conditions and with Hydrotalcite HT-S as Activating Agent.
[
b]
[b]
Entry
N-Protected Amino acid
Amino methyl ester
Dipeptide N-Protected-aa-aa-OMe
Yield (%)
1
2
3
4
5
6
7
8
9
Boc-Leu
Ala
Phe
Val
Ala
Leu
Ile
N-Boc-Leu-Ala (3a)
N-Boc-β-Ala-Phe (3b)
N-Boc-β-Ala-Val (3c)
N-Boc-β-Ala-Ala (3d)
N-Boc-β-Ala-Leu (3e)
N-Boc-β-Ala-Ile (3f)
N-Boc-β-Ala-Gly (3g)
N-Boc-β-Ala-His (3h)
N-Boc-β-Ala-β-Ala (3i)
N-Cbz-Phe-Phe(3j)
N-Cbz-Phe-Ala (3k)
N-Fmoc-Val-Phe (3l)
N-Fmoc-Val-Ala (3m)
89
89
85
79
89
82
78
Boc-β-Ala
Boc-β-Ala
Boc-β-Ala
Boc-β-Ala
Boc-β-Ala
Boc-β-Ala
Boc-β-Ala
Boc-β-Ala
Cbz-Phe
Cbz-Phe
Fmoc-Val
Fmoc-Val
Gly
His
β-Ala
Phe
Ala
Phe
Ala
[
c]
70
73
83
85
83
88
10
11
12
13
[
a] Reaction conditions: N-protected-amino acid (0.25 mmol), amino methyl ester hydrochloride (0.25 mmol), EDC (0.275 mmol), HOBt (0.275 mmol), HT-S (250
mg, 0.41 mmol), Jar-3 of stainless steel (12 mL, 2.1 cm diameter). [b] Yield of isolated product after chromatographic purification. [c] HT-S (400 mg, 0.66 mmol)
was used.
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European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
advantages including short reaction time (75 min), the use of
low-cost, readily available reagents, mild reaction conditions,
easy recovery of the catalyst, and minimization of waste.
Table 4. Recycling of the Hydrotalcite Activating Agent in the Synthesis of ,-
[
a]
Dipeptidic Derivative 3b
.
Experimental Section
[
b]
Entry
Catalyst
Cycle
[b]
Yield (%)
General Remarks: All reagents and solvents were obtained from
Sigma–Aldrich and were used without further purification, unless
otherwise stated. Commercial N-ethyl-N´-(3-dimethylaminopropyl)
carbodiimide hydrochloride (EDC), 1-hydroxy benzotriazole (HOBt) and
[250 mg]
1
2
3
4
5
HT-S
1
2
3
4
3
81
75
57
43
83
HT-S
6 2 3 2
Hydrotalcite Synthetic® (Mg Al (CO )(OH)16·4H O) were also acquired
HT-S
from Sigma-Aldrich. Flash column chromatography was performed with
Silica gel. Mechanochemical experiments were carried out in a Retsch
MM200 ball mill that was equipped with one of three possible types of
reactors: Jar-1, an agate mill jar (5 mL, 1.2 cm diameter) equipped with
two balls of agate (diameter: 6 mm; mass: 0.44 g); Jar-2, stainless steel
mill jar (6 mL, 1.2 cm diameter) equipped with one (or two) ball mill(s)
HT-S
[
c]
HT-R
[
a] Reaction conditions: N-Boc-β-ala 1b (0.25 mmol), L-phenylalanine methyl
ester hydrochloride 2b (0.25 mmol), EDC (0.275 mmol), HOBt (0.275 mmol).
b] Yield of isolated product (3b) after chromatographic purification. [c]
(
diameter: 6 mm, mass 1.52 g); Jar-3, a stainless steel mill jar (12 mL,
2.1 cm diameter) equipped with one (or two) stainless steel ball(s)
diameter: 9.0 mm; mass: 5.6 g). FTIR-ATR spectra were recorded with a
[
Reconstructed hydrotalcite HT-S after second recycle.
(
Finally, when the synthesis of dipeptidic derivative 3a was
carried out at the larger scales of 1 and 2 mmol, the observed
yields were 76 and 60%, respectively (for experimental details
see Supporting Information). This decrease in yield can be
attributed to an unfavorable reaction medium (sticky and
viscous) and slow mass transfer, as previously discussed by
Bonnamour and coworkers. In order to improve the mixing of
the reagents in the ball mill, a few drops of solvent (“minimal
solvent”) were added. This strategy is called solvent-assisted
Perkin–Elmer (PC16, Spectrum GX) FTIR/FIR spectrometer with
attenuated total reflectance (ATR). The NMR spectroscopic data were
recorded on Jeol ECA (500 MHz) and Bruker DP300 (300 MHz)
1
spectrometers. H NMR chemical shifts are in parts per million (ppm) and
coupling constants in hertz (Hz). The multiplicities of the NMR signals are
reported by using the following abbreviations: s (singlet), br s (broad
singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Melting
points (mp) were measured with a Büchi B-540 instrument. High-
resolution mass spectra were recorded with an LC/MSD-TOF Agilent
mass spectrometer. The hydrotalcites were characterized by powder
XRD with Cu-Kα1 radiation, using a D-500 SIEMENS diffractometer
[17]
[
18]
grinding (LAG).
In this context, a recent study by Porte and
[7d]
coworkers recommends the use of EtOAc and γ-valerolactone
as green additives in α-peptide mechanosynthesis. Therefore,
we examined to use EtOAc as liquid additive in the reaction.
Furthermore, in view of the remarkable characteristics of N,N′-
(equipped with a graphite monochromator) in the range from 4 to 75◦ (2θ)
and FTIR-ATR.
[
19]
dimethyl-N,N′-propyleneurea (DMPU),
this solvent was also
examined in LAG. Indeed, cyclic urea DMPU is a polar, aprotic
solvent, water soluble in any ratio and can be used as
replacement of toxic DMF. Besides DMPU has shown its
Activation of hydrotalcite: Calcined hydrotalcite (HT-C). This material
was prepared from Hydrotalcite Synthetic® (HT-S) according to the
[
20]
[
19]
procedure reported by Rao and coworkers.
HT-S was heated to 450
effectiveness as a co-solvent in highly nucleophilic reactions.
°C in a tubular furnace (heat rate 5°/min) under air flow for 8 h, and then
With EtOAc and DMPU (0.5 μl per mg of reactants) as LAG
additives the expected dipeptide was obtained in 84 and 83%
yield, respectively (for experimental details see Supporting
Information). Additional studies on the use of DMPU in LAG are
on-going in our laboratories.
cooled to room temperature under nitrogen flow to give HT-C as a white
powder.
Reconstructed hydrotalcite (HT-R). This material was prepared from
[
20]
HT-C according to the procedure reported by Rao and coworkers. The
calcined hydrotalcite (HT-C) was rehydrated at room temperature under
a flow of water vapor and nitrogen for 48 h. The resulting solid was dried
at 100 °C in a tubular furnace under nitrogen flow for two hours to give
HT-R as a white powder.
Conclusions
In summary, this work shows that Mg-Al hydrotalcite-like
materials are efficient basic activators for amidation (peptide
bond formation) of N-protected-amino acids in the presence of
HOBt and EDC, under mechanochemical, solvent-free reaction
conditions. Dipeptidic derivatives were obtained in good to
excellent yields using commercial (HT-S) and reconstructed
hydrotalcite (HT-R), whereas calcined hydrotalcite (HT-C)
afforded lower yields. The present protocol offers several
General procedure for the synthesis of dipeptides 3a-3m. A mixture
of N-protected derivatives of α- or β-amino acids (0.25 mmol), - or -
aminoester hydrochloride (0.25 mmol) and HOBt (0.275 mmol) was
milled in a stainless steel grinding jar (12 mL, 2.1 diameter) equipped
with one stainless steel ball (9 mm diameter, 5.6 g) for 2 min at 25Hz.
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European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
Commercial hydrotalcite HT-S (0.41 mmol) was added and milled for 2
min at 25 Hz. Finally EDC (0.275 mmol) was added and milled for 75 min
at 25 Hz. The resulting crude product mixture was recovered with ethyl
acetate (30 mL) and filtered to remove the hydrotalcite solid material. The
organic phase was washed successively with 10% citric acid solution (2 x
NMR (75 MHz, CDCl
3
) δ 172.5, 171.6, 156.0, 79.2, 57.0, 52.2, 36.6, 36.0,
+
31.10, 28.3, 18.9, 17.8 ppm. HR-ESI-TOF calcd for C14
H N O
27 2 5
[M + H] :
303.1914, found: 303.1915 (0.3 ppm error).
[
13a]
N-Boc-β-Ala-L-Ala-OMe (3d).
N-Boc-β-alanine 1b (0.25 mmol), L-
5
mL), 10% NaHCO
3
solution (2 x 5 mL), 10% K
2
CO
3
solution (2 x 5 mL),
alanine methyl ester hydrochloride 2d (0.25 mmol), HOBt (0.275 mmol),
EDC (0.275 mmol) and commercial hydrotalcite HT-S (250 mg, 0.41
mmol) were allowed to react according to the general procedure for the
synthesis of dipeptides to give 54.1 mg of 3d as a white solid (79% yield),
brine (2 x 5 mL) and dried over anhydrous Na
2
SO
4
. The organic layer
was concentrated in vacuum and the resulting residue was purified by
flash column chromatography on silica gel (hexanes/EtOAc) to give
dipeptides 3a-3m.
2
5
[13a]
mp = 76-79 °C. [α]
D
= + 45.5 (c 0.1, CHCl
3
) [lit.:
mp = 78-80 °C.
)]. (FT-IR/ATR cm ) νmax 3357, 3322, 2983,
) δ 6.33 (1H, br, Ala-NH),
25
D
–1
[
α]
= +55.0 (c 0.1, CHCl
3
[
12]
1
N-Boc-Leu-L-Ala-OMe (3a). N-Boc-Leucine 1a (0.25 mmol), L-alanine
methyl ester hydrochloride 2a (0.25 mmol), HOBt (0.275 mmol), EDC
1745, 1681, 1646. H NMR (300 MHz, CDCl
3
5.21 (1H, br-s, β-Ala- NH), 4.56 (1H, q, CH, J = 7.2 Hz), 3.73 (3H, s,
OCH ), 3.39 (2H, m, CH NBoc), 2.42 (2H, t, CH C=O, J = 5.8 Hz), 1.41
(9H, s, t-Bu), 1.38 (3H, s,CH ) ppm. C NMR (75 MHz, CDCl ) δ 173.4,
(0.275 mmol) and commercial hydrotalcite HT-S (250 mg, 0.41 mmol)
3
2
2
13
were allowed to react according to the general procedure for the
3
3
synthesis of dipeptides to give 70 mg of 3a as a white solid (89% yield),
171.1, 156.1, 79.3, 52.5, 48.0, 36.5, 36.0, 28.3, 18.3 ppm. HR-ESI-TOF
2
5
[12]
+
mp = 110-114 °C; [α]
D
=46.8 (c 0.33 in MeOH), [lit.
mp 113-114 °C;
calcd for C12
H
23
N
2
O
5
[M + H] : 275.1601, found: 275.1604 (0.8 ppm
25
D
–1
[
α]
= 49.2 (c 0.0116 in MeOH)]. (FT-IR/ATR cm ) νmax 3440, 2966,
error).
1
2
5
3
931, 1700, 1511. H NMR (500 MHz, CDCl
3
): δ 6.81 (1H, br s, Ala-NH),
),
i-Bu), 1.42-1.48 (1H, m, CHi-
), 0.90 (6H, t, CH i-
): δ 173.1, 172.1, 155.6, 80.1,
3.0, 52.4, 48.0, 41.3, 28.3, 24.7, 22.9, 22.0, 18.3. HR-ESI-TOF calcd for
[
13a]
.02 (1H, br, Leu-NH), 4.52 (1H, q, J = 7.2 Hz), 4.12 (1H, br, CHCO
.70 (3H, s, OCH ), 1.67-1.57 (2H, m, CH
2
N-Boc-β-Ala-L-Leu-OMe (3e).
N-Boc-β-alanine 1b (0.25 mmol), L-
3
2
Leucine methyl ester hydrochloride 2e (0.25 mmol), HOBt (0.275 mmol),
EDC (0.275 mmol) and commercial hydrotalcite (250 mg, 0.41 mmol)
were allowed to react according to the general procedure for the
synthesis of dipeptides to give (70.3 mg, 89% yield) of 3e as a white
Bu), 1.40 (9H, s, t-Bu), 1.35 (3H, d, J = 7.1 Hz, CH
3
3
13
Bu, J = 6.1 Hz). C NMR (125 MHz, CDCl
3
5
+
25
D
[13a]
C H N O
15 28 2 5
[M + H] : 317.2070, found: 317.2071 (0.1 ppm error).
solid, mp = 49-52 °C. [α]
= +12.9 (c 0.3, CHCl
3
) [lit.
mp = 50-52 °C.
25
D
–1
[
α]
3
= + 5.5 (c 0.1, CHCl )]. (FT-IR/ATR cm ) νmax 3351, 2956, 2933,
[
21]
1
N-Boc-β-Ala-L-Phe-OMe (3b).
N-Boc-β-alanine 1b (0.25 mmol), L-
1753, 1691, 1650. H NMR (500 MHz, CDCl
3
) δ 6.68 (1H, br, Leu-NH),
phenylalanine methyl ester hydrochloride 2b (0.25 mmol), HOBt (0.275
5.31 (1H, br-s, β-Ala-NH), 4.49 (1H, m, (CHCO
3.29 (2H, m, CH NBoc), 2.35 (2H, m, CH C=O), 1.60-1.49 (2H, m, CH
Bu), 1.48-1.41 (1H, m, CHi-Bu), 1.31 (9H, s, t-Bu), 0.88 (6H, d,CH
2
)), 3.61 (3H, s, OCH
3
),
mmol), EDC (0.275 mmol) and commercial hydrotalcite HT-S (250 mg,
2
2
2
i-
0.41 mmol) were allowed to react according to the general procedure for
3
i-Bu, J
13
the synthesis of dipeptides to give 78.3 mg of 3b as a white solid (89%
= 5.8 Hz) ppm. C NMR (75 MHz, CDCl
3
) δ 173.5, 171.5, 156.1, 79.2,
25
D
[21]
yield), mp = 92–94 °C. [α]
= + 58.8 (c 1.0, CHCl
3
), [lit. mp 91-92 °C.
56.2, 52.6, 41.1, 36.6, 36.0, 28.3, 24.8, 22.7, 21.7 ppm. HR-ESI-TOF
25
D
–1
+
[
α]
= +51.0 (c 1.0, CHCl
3
)] . (FT-IR/ATR cm ) νmax 3359, 3313, 29763,
calcd for C15H N O
29 2 5
[M + H] : 317.2070, found: 317.2073 (0.5 ppm
1
1
739, 1681, 1646. H NMR (350 MHz, CDCl
3
) δ 7.30-7.23 (3H, m, H-Ar),
error).
1
7
.09-7.07 (2H, d, Hortho-Ar, J = 7.0 Hz), 6.12 ( H, br, Phe-NH), 5.12 (1H,
[
13a]
br-s, β- Ala-NH), 4.86 (1H, m, CH), 3.72 (3H, s, OCH
CH NBoc), 3.13, (1H, dd,CH Ph, J = 5.6, 13.8 Hz), 3.05 (1H, dd, CH
J = 6.2, 13.8 Hz), 2.36 (2H, t, CH C=O, J = 5.6 Hz),1.44 (9H, s, t-Bu)
) 172.0, 171.2, 156.1, 135.8, 129.3,
28.7, 127.3, 79.4, 53.2, 52.5, 38.0, 36.6, 36.2, 28.5 ppm. HR-ESI-TOF
3
), 3.35 (2H, m,
N-Boc-β-Ala-L-Ile-OMe (3f).
N-Boc-β-alanine 1b (0.25 mmol), L-
2
2
2
Ph,
isoleucine methyl ester hydrochloride 2f (0.25 mmol), HOBt (0.275
mmol), EDC (0.275 mmol) and commercial hydrotalcite HT-S (250 mg,
0.41 mmol) were allowed to react according to the general procedure for
the synthesis of dipeptides to give 64.8 mg of 3f as a gummy solid (82%
2
13
ppm. C NMR (125 MHz, CDCl
3
1
+
25
D
[13a]
25
D
calcd for C18H N O
27 2 5
[M + H] : 351.1914, found: 351.1915 (0.1 ppm
yield), [α]
= +12.31 (c 0.3, CHCl
3
), [lit.
[α]
3
= +5.0 (c 0.7, CHCl )].
–1
1
error).
(FT-IR/ATR cm ) νmax 3317, 2966, 2927,1743, 1693, 1634. H NMR (300
MHz, CDCl
m, NCH), 3.69 (3H, s, OCH
CH C=O), 1.83 (1H, m, CH), 1.37 (10H, m, CH
(1H, m, CH
3
) δ 6.23 (1H, br, Ile-NH), 5.20 (1H, br-s, β-Ala-NH), 4.53 (1H,
), 3.36 (2H, m, CH NBoc), 2.41 (2H, m,
CH , t-Bu), 1.17-1.04
) ppm. C NMR (75 MHz, CDCl ) δ
[
13a]
N-Boc-β-Ala-L-Val-OMe (3c).
N-Boc-β-alanine 1b (0.25 mmol), L-
3
2
valine methyl ester hydrochloride 2c (0.25 mmol), HOBt (0.275 mmol),
EDC (0.275 mmol) and commercial hydrotalcite HT-S (250 mg, 0.41
mmol) were allowed to react according to the general procedure for the
synthesis of dipeptides to give 64.2 mg of 3c as a gummy solid (85%
2
2
3
13
2
CH
3
), 0.87 (6H, m, 2CH
3
3
172.5, 171.5, 156.0, 79.1, 56.3, 52.0, 37.6, 36.6, 35.9, 28.3, 25.1, 15.4,
+
11.4 ppm. HR-ESI-TOF calcd for C15
H N O
29 2 5
[M + H] : 317.2070, found:
25
D
[13a]
25
yield). [α]
= +9.0 (c 1.6, CHCl
3
), [Lit.
D 3
[α] = +12.0 (c 1.6, CHCl )].
317.2071 (0.1 ppm error).
–1
1
(
FT-IR/ATR cm ) νmax 3340, 3324, 2958, 2919, 1735, 1689, 1650.
H
[
13a]
NMR (300 MHz, CDCl
3
) δ 6.35 (1H, br, Val-NH), 5.25 (1H, br-s, β-Ala-
)), 3.68 (3H, s, OCH ), 3.36 (2H, m,
C=O), 2.15 (1H, m, (CH)), 1.38 (9H, s, t-Bu),
N-Boc-β-Ala-Gly-OMe (3g).
N-Boc-β-alanine 1b (0.25 mmol), L-
NH), 4.50 (1H, m, (CHCO
CH NBoc), 2.44 (2H, m, CH
.92 (3H, d, CH , J = 6.8 Hz), 0.89 (3H, d, CH
2
3
glycine methyl ester hydrochloride 2g (0.25 mmol), HOBt (0.275 mmol),
EDC (0.275 mmol) and commercial hydrotalcite (250 mg, 0.41 mmol)
were allowed to react according to the general procedure for the
2
2
13
0
3
3
, J = 6.8 Hz) ppm.
C
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European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
[
7e]
synthesis of dipeptides to give 50.7 mg 3g as a liquid (78% yield). (FT-
N-Cbz-Phe-L-Ala-OMe (3k).
N-Cbz-L-Phenylalanine 1c (0.25 mmol),
–
1
1
IR/ATR cm ) νmax 3309, 2915, 2846, 1739, 1639, 1662. H NMR (300
MHz, CDCl ) δ 6.67 (1H, br, Gly-NH), 5.30 (1H, br-s, β-Ala- NH), 3.98
2H, d, CH CO , J = 5.36 Hz), 3.70 (3H, s, OCH ), 3.36 (2H, q, CH NBoc,
J = 5.9 Hz), 2.43 (2H, t, CH C=O, J = 5.7 Hz), 1.37 (9H, s, t-Bu) ppm.
L-alanine methyl ester hydrochloride 2d (0.25 mmol), HOBt (0.275 mmol),
EDC (0.275 mmol) and commercial hydrotalcite (250 mg, 0.41 mmol)
were allowed to react according to the general procedure for the
synthesis of dipeptides to give 81.9 mg 3k as a white solid (85% yield),
3
(
2
2
3
2
13
2
C
25
D
[7e]
NMR (75 MHz, CDCl
3
) δ 172.0, 170.4, 156.1, 79.2, 52.3, 41.1, 36.5,
mp 142-144 °C. [α]
= + 7.2 (c 0.33, CHCl
3
), [lit.
mp 126.0-127.0 °C;
+
25
–1
3
5.9, 28.3 ppm. HR-ESI-TOF calcd for C11
H N O
21 2 5
[M + H] : 261.1444,
[α]
D
= 24.1 (c 1.10, EtOH)]. (FT-IR/ATR cm ) νmax 3295, 3058, 3027,
1
found: 261.1443 (0.5 ppm error).
2950, 1741, 1691, 1648, 1533, 1259, 1216. H NMR (500 MHz, CDCl
3
) δ
7.14-7.34 (10H, m, 2Ar), 6.54 (1H, d, J = 7.5 Hz, Ala-NHCO), 5.46 (1H, d,
[
22]
N-Boc-β-Ala-L-His-OMe (3h).
N-Boc-β-alanine 1b (0.25 mmol), L-
Phe-NHCO, J = 9.0 Hz), 5.0 (2H, m, OCH
2
Ph), 4.52-4.44 (2H, m, 2CH),
, J
3
) δ 172.95, 170.59, 156.02, 136.36,
histidine methyl ester dihydrochloride 2h (0.25 mmol), HOBt (0.275
3 2 3
3.69 (3H, s, OCH ), 3.05 (2H, d, CH Ph, J = 6.4 Hz), 1.31 (3H, d, CH
13
mmol), EDC (0.275 mmol) and commercial hydrotalcite HT-S (400 mg,
= 7.0 Hz). C NMR (125 MHz, CDCl
0.66 mmol) were allowed to react according to the general procedure for
136.25, 129.47, 128.75, 128.63, 128.29, 128.12, 127.12, 67.13, 56.08,
+
the synthesis of dipeptides (not washed with citric acid solution) to give
52.57, 48.21, 38.63, 18.32. HR-ESI-TOF calcd for C21
H N O
24 2 5
[M + H] :
25
5
D
9.7 mg of 3h as a white solid (70% yield), mp 77-81 °C. [α] = + 5.0 (c
385.1763, found: 385.1759 (0.3 ppm error).
[
22]
22
D
0
.35, CH
3
OH), [lit. mp 76–78 °C; [α]
+5.85 (c 0.29, MeOH)]. (FT-
–
1
1
[7e]
IR/ATR cm ) νmax 3318, 2977, 2915, 1737, 1685, 1646, 1527. H NMR
N-Fmoc-Val-L-Phe-OMe (3l). N-Fmoc-L-valine 1d (0.25 mmol), L-phe
methyl ester hydrochloride 2b (0.25 mmol), HOBt (0.275 mmol), EDC
(0.275 mmol) and commercial hydrotalcite HT-S (250 mg, 0.41 mmol)
were allowed to react according to the general procedure for the
synthesis of dipeptides to give 103.0 mg 3l as a white solid (83% yield),
(
500 MHz, CDCl
.74 (1H, s, C=CHNH), 5.60 (1H, t, β-Ala-NH, J = 5.7 Hz), 4.74 (1H, m,
CH), 3.65 (3H, 2, OCH ), 3.36 (2H, m, CH NBoc), 3.0 (2H,d, CH , J = 5.1
Hz), 2.39 (2H, t, CH C=O, J = 5.9 Hz), 1.39 (9H, s, t-Bu) ppm. C NMR
125 MHz, CDCl ) δ 172.0, 171.8, 156.3, 135.4, 135.0, 115.9, 79.4, 52.8,
2.5, 36.9, 36.4, 29.0, 28.4 ppm. HR-ESI-TOF calcd for C15 [M +
3
) δ 7.50 (1H, s, N=CHNH), 7.35 (1H, br-s, His-NHCO),
6
3
2
2
13
2
25
D
[7e]
(
3
mp 182–184 ºC. [α]
= + 9.8 (CHCl
3
, c = 0.6, CHCl
3
), [lit. mp = 182-
25
D
–1
5
25
H N
4
O
5
183 ºC; [α]
1727, 1685, 1651, 1533 cm ; H NMR (500 MHz, CDCl
7.6 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.30 (t, J
= +15.9 (c 1.02, CHCl )]. (FT-IR/ATR cm ) νmax 3281,
3
+
-1
1
H] : 341.1823, found: 341.1822 (0.74 ppm error).
3
) δ 7.75 (d, J
=
[
13a]
N-Boc-β-Ala-β-Ala-OMe (3i).
N-Boc-β-alanine 1b (0.25 mmol), β-
= 7.2 Hz, 2H), 7.25-7.14 (m, 3H), 7.06 (d, J = 3.6 Hz, 2H), 6.38 (d, J = 7.9
Hz, 1H), 5.41 (d, J = 7.2 Hz, 1H), 4.88 (m, 1H), 4.42 (m, 1H), 4.29 (t, J =
6.8 Hz, 1H), 4.203 (t, J = 6.8 Hz, 1H), 4.02 (m, 1H), 3.69 (s, 3H), 3.16-
3.04 (m, 2H), 2.11-2.01 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.5
alanine methyl ester hydrochloride 2i (0.25 mmol), HOBt (0.275 mmol),
EDC (0.275 mmol) and commercial hydrotalcite HT-S (250 mg, 0.41
mmol) were allowed to react according to the general procedure for the
synthesis of dipeptides to give 50 mg of 3i as a white solid (73% yield),
13
Hz, 3H); C NMR (125 MHz, CDCl
3
) 170.1, 170.9, 156.3, 143.9, 141.3,
[
13a]
–1
mp = 76-78 C, [lit.
mp = 77-78 °C]. (FT-IR/ATR cm ) νmax 3359, 2973,
135.6, 129.2, 128.7, 127.8, 127.3, 127.1, 125.2, 120.09, 67.1, 60.2, 53.1,
1
2
915, 1731, 1681, 1643. H NMR(300 MHz, CDCl
3
) δ 6.37 (1H, br, β-Ala-
), 3.48 (2H,
C=O, J = 5.9 Hz), 2.53 (2H, t,
CO , J = 5.9 Hz), 1.41 (9H, s, t-
) δ 172.9, 171.5, 156.0, 79.2, 51.8,
6.5, 36.1, 34.7, 33.7, 28.3 ppm. HR-ESI-TOF calcd for C12 [M +
32 2 5
52.4, 47.2, 37.9, 31.3, 19.1, 17.9. HR-ESI-TOF calcd for C30H N O [M +
+
NH), 5.23 (1H, br-s, β-Ala-BocNH), 3.67 (3H, s, OCH
q,CH NBoc, J = 5.9 Hz), 3.35 (2H, q,CH
CH NHCO, J = 5.9 Hz), 2.36 (2H, t, CH
Bu) ppm. C NMR (75 MHz, CDCl
3
H] : 501.2383, found: 501.2386 (0.5 ppm error).
2
2
[
7e]
2
2
2
N-Fmoc-Val-Ala-OMe (3m).
Fmoc-L-valine 1d (0.25 mmol), L-ala
13
3
methyl ester hydrochloride 2a (0.25 mmol), HOBt (0.275 mmol), EDC
(0.275 mmol) and commercial hydrotalcite HT-S (250 mg, 0.41 mmol)
were allowed to react according to the general procedure for the
synthesis of dipeptides to give 93.8 mg 3m as a white solid (88% yield),
3
23 2 5
H N O
+
H] : 275.1601, found: 275.1614 (0.3 ppm error).
[
23]
25
[7e]
N-Cbz-Phe-L-Phe-OMe (3j).
N-Cbz-L-Phenylalanine 1c (0.25 mmol),
mp = 208-211°C. [α]
D
= 18.1 (CHCl
3
, c = 1.05), [Lit. mp = 205-207
26
D
–1
L-phenylalanine methyl ester hydrochloride 2b (0.25 mmol), HOBt (0.275
ºC; [α]
= 18.8 (c 1.00, CHCl
3
)]. (FT-IR/ATR cm ) νmax 3340, 3120,
1
mmol), EDC (0.275 mmol) and commercial hydrotalcite HT-S (250 mg,
1750, 1660, 1520, 1440, 1370, 1345, 1260, 1220. H-NMR (500 MHz,
0.41 mmol) were allowed to react according to the general procedure for
3
CDCl ): δ 7.73 (d, J = 7.3 Hz, 2H), 7.60-7.55 (m, arom. 2H), 7.42-7.34 (m,
the synthesis of dipeptides to give 96.2 mg 3j as a white solid (83%
arom., 2H) , 7.31-7.24 (m, arom. Hz, 2H), 6.67 (br s, 1H), 5.59 (d, 1H, J =
8.8 Hz), 4.57 (q, J = 7.4 Hz, 1H), 4.41 (m, 1H), 4.32 (m, 1H), 4.19 (m, 1H),
25
D
[23]
yield), mp = 136–138 °C. [α]
= + 35.1 (c 0.33, CHCl
3
), [lit.
mp =
2
5
–1
1
3
7
34–136 °C. [α]
D
=21.9 (c 0.01, CHCl
3
)]. (FT-IR/ATR cm ) νmax 3307,
4.07 (m, 1H), 3.71 (s, 3H), 2.13-2.05 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H),
1
13
270, 3033, 2946, 1733, 1687, 1660; 698. H NMR (500 MHz, CDCl
3
) δ
3
0.97 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H) C NMR (CDCl ): δ
.10–7.34 (15H, m, Ar), 6.37 (1H, br s, Phe-NH), 5.35 (1H, br s, Phe-
Ph), 4.78 (1H, br s, CH), 4.45 (1H, d, CH, J = 6.4
173.2, 171.0, 156.5, 143.9, 143.8, 141.3, 127.8, 127.1,125.2, 125.1
NH), 5.04 (2H, m, OCH
2
120.0, 67.1, 60.2, 52.5, 48.1, 47.2, 31.5, 19.1, 18.1, 18.0. HR-ESI-TOF
13
+
Hz), 3.65 (3H, s, OCH
3
), 2.94–3.09 (4H, m, 2CH
2
Ph). C NMR (125
calcd for C24H N O
28 2 5
[M + H] : 425.2076, found: 425.2070 (0.1 ppm
MHz, CDCl
3
) δ 171.4, 170.5, 155.9, 136.3, 136.2, 135.6, 129.4, 129.3,
error).
1
3
4
28.7, 128.6, 128.5, 128.3, 128.12, 127.2, 127.1, 67.15, 56.0, 53.4, 52.4,
+
8.4, 37.9. HR-ESI-TOF calcd for C27
H N O
28 2 5
[M + H] : 461.2070, found: Acknowledgements
61.2077 (1.4 ppm error).
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
The authors thank Consejo Nacional de Ciencia y Tecnología
Portada, I. Đilović, I. Halasz, D. Margetić, Chem. Commun. 2012, 48,
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601276
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Mechanochemistry *
José M. Landeros and Eusebio Juaristi*
Page No. – Page No.
Mechanochemical synthesis of
dipeptides using Mg-Al hydrotalcite
as activating agent under solvent-free
reaction conditions
An efficient protocol for the synthesis of several α,α-, ,- and ,β-dipeptides under
ball-milling activation and solvent-free conditions has been developed. The reaction
takes place in the presence of coupling agents EDC, HOBt, and with Mg-Al
hydrotalcite as activator.
This article is protected by copyright. All rights reserved.