Solvent-free synthesis of unsaturated amino esters in a ball-mill

Article abstract of DOI:10.1016/j.tetlet.2010.09.069

The ball-milling technique was used under solvent-free conditions to perform a Horner-Wadsworth-Emmons reaction in the presence of a mild carbonate base. Starting from a phosphonate-substituted glycine, this method gave access to Boc-protected unsaturated

Full text of DOI:10.1016/j.tetlet.2010.09.069

Tetrahedron Letters 51 (2010) 6246–6249
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-free synthesis of unsaturated amino esters in a ball-mill
⇑
Alice Baron, Jean Martinez, Frédéric Lamaty
Institut des Biomolécules Max Mousseron UMR 5247 CNRS—Université Montpellier 1 et Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2010
Revised 14 September 2010
Accepted 17 September 2010
Available online 15 October 2010
The ball-milling technique was used under solvent-free conditions to perform a Horner–Wadsworth–
Emmons reaction in the presence of a mild carbonate base. Starting from a phosphonate-substituted gly-
cine, this method gave access to Boc-protected unsaturated amino esters in excellent yield and selectivity
in many cases. The scope of the reaction was delineated.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ball-mill
Solvent-free
Amino acid
Horner–Wadsworth–Emmons
Olefination
Dehydroalanine
Carbonate base
Phosphonate
Ball-milling is a mechanochemical technique that is widely ap-
plied to the grinding of minerals into fine particles, to the prepara-
tion, and modification of inorganic solids.1,2 Ball-mill chemistry is
of interest because it is performed in the absence of solvent, under
environmentally friendly conditions. In the last years, this tech-
nique has found interest in synthetic organic chemistry.3,4 The re-
ported examples include nitrone synthesis,5 functionalization of
fullerenes,6 reductive benzylation of malonitrile,7 protection of
amines,8 Knoevenagel reaction,9 aldol condensation10 and its
asymmetric version,11 Michael additions,9 preparation of phospho-
rus ylides,12 oxidative coupling of 2-naphthol,13 Heck,14 Suzuki15
and Sonogashira16 coupling reactions, and peptide synthesis.17
One powerful method for making carbon–carbon bond is the
Wittig reaction starting from carbonyl compounds and making
use of a phosphorus ylide.18 It was shown recently that this reac-
tion could be performed in a ball-mill12 (scheme 1).
no esters.21 The synthesis developed by Schmidt et al.,22 based on
the HWE reaction, is a practical method for making olefinic amino
esters from a carbonyl compound and a phosphonate derivative of
glycine (scheme 2). Nevertheless, it requires usually the use of an
excess of organic base and a low temperature for the deprotona-
tion step is needed.
Few examples of solvent-free HWE reactions have been pub-
lished but very often an excess of liquid reactant serves as the sol-
vent.23a–c Since the Wittig reaction has been explored under
mechanical activation,12 we presumed that the HWE version could
be a viable and powerful approach for the preparation of unsatu-
rated amino esters starting from carbonyl compounds.
R3
P(Ph)3
X
R1
R2
R1 R2
O
The Horner–Wadsworth–Emmons (HWE) version19 of the Wit-
tig reaction focuses on the use of more stabilized phosphonate
ylides. This is a method of choice for the preparation of unsatu-
rated esters (EWG = CO2R). Usually, the phosphonate stabilized
carbanion is sufficiently nucleophilic to react under mild condi-
tions to yield the olefin. As part of our program to prepare unnat-
ural amino acids and use them as building blocks for peptide
synthesis,20 we considered the development of a HWE reaction in
a ball-mill as a valuable route for the synthesis of unsaturated ami-
K2CO3
Ball-milling
R3
Scheme 1. Solvent-free Wittig reaction in a ball-mill.
R1 R2
P(O)(OMe)2
OR4
R1
Base
OR4
+
PG-NH
PG-NH
R2
Solvent
O
O
O
⇑
Corresponding author. Tel.: +33 467143847; fax: +33 467144866.
E-mail address: frederic.lamaty@univ-montp2.fr (F. Lamaty).
Scheme 2. Horner–Wadsworth–Emmons reaction.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.069

A. Baron et al. / Tetrahedron Letters 51 (2010) 6246–6249
6247
Table 1
Reaction conditions for the HWE reaction in a ball-milla
OMe
OMe
MeO
OMe
P(O)(OMe)2
MeO
base
MeO
OMe
OMe
OH
+
+
BocNH
BocNH
BocNH
Ball-Mill
O
O
O
H
O
1
2a
3a
4a
Entry
Base (equiv)
Conversion (%)
Yield (%)
1
2
3
4
5
6
7
8
NaHCO3 (3)
K2CO3 (1)
K2CO3 (3)
KOH (3)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (1.5)
DBU
5
91
93
n.d.c
n.d.
n.d.
n.d.
95
94
n.d.
n.d.
94b
100
100
94
63
a
b
c
Starting materials were ground in a planetary ball-mill for 7 h.
Hydrolysis product 4a was also obtained.
n.d.: not determined.
Reactions in a ball-mill give better results when solid–solid
To investigate the scope of the reaction with various aldehydes
and ketones, we considered their reactions in the presence of
Cs2CO3 or K2CO3. Cs2CO3 was considered as the best base but since
K2CO3 gave satisfactory results, it was also tested because of its
superiority from an economical, ecological, and toxicological point
of view. Eventually, it proved even superior to Cs2CO3 in many
cases. The preparation of various protected amino esters is pre-
sented in Table 2.
reactions are performed.8 Therefore, starting from solid amino-
phosphoryl acetate, we tested the reaction on a solid aldehyde,
3,5-dimethoxybenzaldehyde, and a solid carbonate base. A mix-
ture of aminophosphoryl acetate 1 (1.1 equiv), 3,5-dimethoxy-
benzaldehyde 2a (1 equiv) and a base (1–3 equiv) was ground
in a planetary ball-mill. In order to reduce the purification steps,
a conversion close or equal to 100% was needed. The reaction
mixture was analyzed by HPLC to evaluate the conversion of
the starting materials and the formation of the expected product.
Results are summarized in Table 1. Generally, reaction time infe-
rior to 7 h led to incomplete conversion. Sodium bicarbonate gave
a very low conversion (entry 1). Potassium carbonate (entry 2)
gave a good conversion albeit not total even if the number of
equivalents was increased (entry 3). In those cases, the HWE
reaction product 3a was obtained.24 This was actually not the
case for the reaction with potassium hydroxide (entry 4). The
reaction was not very clean and the major product, along with
some starting material and expected 3a, was 4a arising from
the concomitant saponification of 3a. The best results were ob-
tained with cesium carbonate (entries 5–7). The initial amount
of base (3 equiv) could be lowered to 2 equiv but not further (en-
try 7). In these cases, the expected product 3a was obtained, in
good yield when the conversion was complete. Finally, DBU that
is the common base use in the Schmidt route was also tested (en-
try 8) but yielded a limited conversion. For the sake of compari-
son, the reaction was carried out in a flask with a stir bar using
the conditions from entry 6 (cesium carbonate as a base). In the
absence of heating, an incomplete conversion (43%) was obtained.
This was not improved by heating to 50 °C since only 45% conver-
sion was obtained, showing the importance of mechanical activa-
tion in this reaction.
Generally, aromatic aldehydes (entries 1–6) reacted efficiently
with complete conversion in most of the cases. Even a hindered
ortho-substituted aryl aldehyde, such as 2b (entry 2) gave an
excellent result. For this series, the Z/E selectivity was very high
since only the Z isomer could be detected, except in the case of
naphthaldehyde 2f (entry 6) where the proportion is in favor of
the same isomer but with a lower selectivity. Even if reaction
conditions were tested on the formation of 3a, starting from so-
lid aldehyde 2a (entry 1), liquid aldehydes also gave satisfying
results (entries 3–6). Among the aliphatic aldehydes (entries 7–
10), n-butyraldehyde 2g, a linear aldehyde, gave the best results
in term of yields and selectivity (entry 7). Conversions of mono-
substituted methanals 2h and 2i (entries 8 and 9) were very
good but the selectivity was poor. t-Butyraldehyde 2j, most
probably too hindered, was not very reactive and full conversion
could not be obtained. Finally, the two ketones 2k and 2l which
were tried in this reaction were unreactive. The HWE reaction of
ketones for the synthesis of tetra-substituted alkenes is a more
demanding process due to the steric hindrance involved between
the two reactants, especially in the present study for the prepa-
ration of dehydro amino esters. In solution in the presence of so-
dium hydride, as stated by Schmidt et al.,22c ketones are
unreactive unless activated. Better results were obtained with
DBU.22a In the ball-mill, only di- and tri-substituted olefins were
synthesized using the Wittig reaction.12 The carbonate bases
used in this study are probably not adapted to less reactive
electrophiles.
When the conversion was complete, a work up using a mini-
mum amount of solvent was performed. Ethyl acetate was added
and the solution was washed with water, dried, evaporated and fil-
tered on a silica gel pad to give amino ester 3a with an excellent
purity and yield.25 In this reaction, only one isomer was obtained
and characterized by 1H and 13C NMR. In contrast to the Wittig
reaction in a ball-mill,12 the stereochemical outcome of the reac-
tion in the ball-mill is the same as in solution. Only the Z isomer
could be detected by NMR.
In conclusion, the Horner–Wadsworth–Emmons reaction could
be performed in the absence of solvent in a ball-mill. This repre-
sents a practical method for the preparation of Boc-protected
unsaturated amino esters, with excellent yield and selectivity in
many cases, making use of mild and inexpensive conditions. Fur-
ther work to scale up this reaction is in progress.

6248
A. Baron et al. / Tetrahedron Letters 51 (2010) 6246–6249
Table 2
Synthesis of amino esters in a ball-mill
R1 R2
P(O)(OMe)2
OMe
base
OMe
R1
+
BocNH
BocNH
Ball-Mill
O
O
R2
2a-l
O
1
3a-l
Entry
1
Electrophile
Physical state mp (°C)
Base
Conversion (%)
Product
Yield (%)
95
Z/E ratio
MeO
OMe
Br
Solid 44–48
Cs2CO3
100
3a
100/0
CHO
2
3
4
Solid 16–19
Liquid
K2CO3
K2CO3
K2CO3
96
100
100
3b
3c
3d
85
88
82
100/0
100/0
100/0
CHO
N
CHO
Liquid
CHO
O
5
6
Liquid
Liquid
Cs2CO3
K2CO3
100
100
3e
3f
89
76
100/0
82/18
CHO
CHO
CHO
7
8
Liquid
Liquid
K2CO3
K2CO3
100
100
3g
3h
80
61
100/0
66/44
CHO
9
Liquid
Liquid
K2CO3
K2CO3
100
35
3i
3j
90
61/39
100/0
CHO
CHO
10
n.d.
11
12
Solid
K2CO3
K2CO3
0
0
3k
3l
0
0
—
—
O
Liquid
O
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Acknowledgments
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24. All new compounds were characterized by 1H and 13C NMR, mass
spectrometry, and high resolution mass spectrometry.
25. Procedure for the preparation of (Z)-methyl 2-[(tert-butoxycarbonyl)amino]-3-
(3,5-dimethoxyphenyl)acrylate 3a: methyl 2-[(tert-butoxycarbonyl)amino]
-2-(dimethoxyphosphoryl)acetate (157 mg, 0.53 mmol), 3,5-dimethoxybenz-
aldehyde (80 mg, 0.48 mmol) and cesium carbonate (314 mg, 0.96 mmol) were
introduced in
a 12 mL grinding jar with five stainless steel balls (7 mm
diameter). The grinding jar was placed in a planetary ball-mill and stirred at
550 rpm during 7 h. EtOAc was added in the jar and the mixture was washed
with water, dried over MgSO4, concentrated under vacuo. The residue was
filtered on a silica gel pad (eluent: cyclohexane/EtOAc, 1:1) to afford 165 mg of
the titled compound (100%) as a white powder: mp 108–109 °C; 1H NMR
(CDCl3, Me4Si) d 1.30 (br s, 9H, C(CH3)3), 3.72 (s, 6H, 2 Â OMe), 3.95 (s, 3H,
OMe), 6.37 (t, J = 2.2 Hz, 1H, CH), 6.63 (d, J = 2.0 Hz, 2H, 2 Â CH), 7.09 (1H, s,
CH). 13C NMR (CDCl3, Me4Si) d 28.10 (C(CH3)3), 52.62 (OCH3), 55.32 (2OCH3),
81.02 (C), 101.67 (CH), 107.46 (2CH), 125.18 (CH), 129.76 (C), 135.76 (C),
152.74 (C@O), 160.66 (2C), 165.96 (C@O); high resolution MS calcd for
C
17H24NO6: 338.1604. Found: 338.1599 [M+H]+.