A concise three-component synthesis of α-amino esters derived from phenylglycine and phenylalanine

Article abstract of DOI:10.1016/j.tetlet.2008.09.137

α-Amino esters have been synthesized using a straightforward three-component reaction among preformed or in situ-generated aromatic or benzylic organozinc reagents, primary or secondary amines and ethyl glyoxylate. The procedure, which is characterized by its simplicity, allows the concise synthesis of phenylglycine and phenylalanine derivatives.

Full text of DOI:10.1016/j.tetlet.2008.09.137

Tetrahedron Letters 49 (2008) 7121–7123
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A concise three-component synthesis of
a-amino esters
derived from phenylglycine and phenylalanine
*
Caroline Haurena, Stéphane Sengmany, Paul Huguen, Erwan Le Gall , Thierry Martens, Michel Troupel
Électrochimie et Synthèse Organique, Institut de Chimie et des Matériaux Paris Est, ICMPE, UMR 7182 CNRS—Université Paris 12 Val-de-Marne, 2-8 rue Henri Dunant,
94320 Thiais, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Accepted 24 September 2008
Available online 27 September 2008
a
-Amino esters have been synthesized using a straightforward three-component reaction among pre-
formed or in situ-generated aromatic or benzylic organozinc reagents, primary or secondary amines
and ethyl glyoxylate. The procedure, which is characterized by its simplicity, allows the concise synthesis
of phenylglycine and phenylalanine derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
a-Amino acids constitute one of the most important families of
ative in the procedure to provide an instant access to a variety of
natural products and play central roles both as building blocks of
proteins and as intermediates in metabolism. They are continu-
ously employed in the elaboration of peptides and as chiral pool
in ligand design and multistep synthesis.1 Amino acids also consti-
tute attractive building blocks in combinatorial chemistry or drug
discovery and in the past years there has been an increasing
interest in various approaches that access novel non-proteinogenic
a
-amino esters.
As a starting point of the study, we imagined to apply the exper-
imental conditions employed in our previous works regarding the
multicomponent coupling of arylzinc reagents, aromatic aldehydes
and secondary amines to the synthesis of
a-amino esters. In this
purpose, it was simply envisaged to replace aromatic aldehydes
by a non acidic glyoxylic acid equivalent under the form of ethyl
glyoxylate.8 The fate of the expected three-component coupling
is depicted in Scheme 1.
Thus, arylzinc reagents (>2 equiv) were preformed in acetoni-
trile from aryl bromides using zinc dust and cobalt catalysis,9
and allowed to react with secondary amines (1 equiv) and ethyl
glyoxylate (1.3 equiv) at room temperature. Results were generally
unsatisfactory with only moderate conversion of the substrates
a
-amino acid derivatives.2
Although numerous methods allow the efficient preparation of
-amino acid derivatives, only a limited set of examples employing
a
multicomponent procedures have been disclosed to date. For in-
stance, the Petasis three-component reaction3 among boronic
acids, amines and glyoxylic acid has been efficiently employed
for the diastereoselective synthesis of pyrrolidine-derived arylgly-
cines4 or the one-pot sequential Petasis-type
a-amino ester forma-
into the expected a-amino esters after a 4 h period. However, a real
tion and palladium-catalyzed cyclization process.5 However,
despite the fact that this method affords a very convenient access
improvement was obtained by simply heating the solution at 50 °C
for several hours.10 In a second step, we envisaged to extend the
procedure to functionalized benzylzinc reagents and noticed from
preliminary experiments that under standard conditions, these re-
agents were clearly more reactive than arylzinc compounds. Fur-
thermore, having shown in a previous work that benzyl bromide
can be easily activated in situ using zinc dust in the presence of
aldehydes and amines to afford coupling products in excellent
yields,7d we chose to simplify the process by operating under these
Barbier-like conditions. Thus, functionalized benzyl bromides
(2.2 equiv) were allowed to react with amines (1 equiv) and ethyl
to a variety of a-amino acid derivatives, the procedure is featured
by rather important reaction times and the impossibility to operate
with some electron-deficient arylboronic acids. Furthermore, to
the best of our knowledge, there is no mention of the use of func-
tionalized benzylzinc reagents in one-step multicomponent proce-
dures leading to
Our group has recently developed a multicomponent procedure
allowing the efficient formation of a range of -substituted amines
a
-amino esters derived from phenylalanine.6
a
such as diarylmethylamines, 1,2-diarylethylamines or benzylam-
ines starting from preformed or in situ-generated organozinc re-
agents, amines and aldehydes.7 Herein, we report preliminary
results regarding the use of ethyl glyoxylate as the aldehyde deriv-
R
R'
FG
N
R
R'
ZnBr
O
H
FG
N
H
EtO2C
+
+
CO2Et
* Corresponding author. Tel.: +33 (0) 149781135; fax: +33 (0) 149781148.
E-mail address: legall@glvt-cnrs.fr (E. Le Gall).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.137

7122
C. Haurena et al. / Tetrahedron Letters 49 (2008) 7121–7123
glyoxylate (1.3 equiv) in the presence of zinc dust at room temper-
ature.11 Results with respect to the use of both aromatic and benz-
ylic bromides in the three-component coupling are presented in
Table 1.
Results range from satisfactory for aryl bromides (entries 1–4)
to excellent for benzyl bromides (entries 6–10). It can be noted that
the nature of functionalities might be of minor importance for
the efficiency of reactions since the three-component coupling
Table 1
Three-component coupling between organic bromides, amines and ethyl glyoxylate
R2
R3
Conditionsa
MeCN
R2 R3
N
R1 Br
N
H
+
EtO2C CHO
+
R1 CO2Et
Entry
1
Organic bromide
Amine
Time (h)
Product
Isolated yield (%)
N
3
4
4
4
66
MeO
Br
N
H
CO2Et
MeO
O
O
N
2
3
4
55
50
60
N
H
Br
O
O
CO2Et
F3C
N
N
H
F3C
Br
CO2Et
N
Br
Br
N
H
CO2Et
H
N
H
5
6
2
1
—
—
N
93
N
H
Br
CO2Et
OMe
OMe
F
F
H
7
8
1
1
1
1
67
77
80
87
H
N
H
N
Br
CO2Et
NC
NC
H
N
H
N
H
Br
CO2Et
CF3
H
CF3
H
N
H
N
9
Br
Br
CO2Et
CO2Et
Cl
Cl
Cl
N
10
N
H
Cl
a For a functionalized bromobenzene as the halide, the organozinc compound is preformed using Zn dust and CoBr2 as a catalyst. The following three-component coupling is
carried out at 50 °C. For a functionalized benzyl bromide as the halide, the substrate is activated in situ using Zn dust only and the reaction is conducted at ambient
temperature.

C. Haurena et al. / Tetrahedron Letters 49 (2008) 7121–7123
7123
F. L.; Schoemaker, H. E.; Blaauw, R. H.; Rutjes, F. P. J. T. Org. Biomol. Chem. 2005,
3, 3435–3467; (e) Kazmaier, U. Angew. Chem., Int. Ed. 2005, 44, 2186–2188.
2. (a) Williams, R. M. Synthesis of Optically Active Amino Acids; Pergamon Press,
Oxford University Press, 1989; (b) Duthaler, R. O. Tetrahedron 1994, 50, 1539–
1650; (c) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998, 63,
3528–3529; (d) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Eur. J. 2002, 8,
3646–3652; (e) Park, H.; Jeong, B.; Yoo, M. S.; Lee, J.; Park, M.; Lee, Y. J.; Kim, M.;
Jew, S. Angew. Chem., Int. Ed. 2002, 41, 3036–3038.
Zn dust
N
Br
+
O
H
CoBr2 10 mol%
CO2Et
EtO2C
+
EtO2C
N
H
CH3CN, 50 °C
N
3. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–586; (b)
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 48, 16463–16470;
(c) Petasis, N. A.; Zavialov, A. J. Am. Chem. Soc. 1997, 119, 445–446; (d) Petasis,
N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–11799; (e) Petasis, N. A.;
Boral, S. Tetrahedron Lett. 2001, 42, 539–542; (f) Prakash, G. K. S.; Mandal, M.;
Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org. Chem. 2002, 67, 3718–3723.
4. Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46, 2025–2028.
5. Grigg, R.; Sridharan, V.; Thayaparan, A. Tetrahedron Lett. 2003, 44, 9017–9019.
6. Katritzky described the displacement of preformed benzotriazole-derived
iminium equivalents by organometallics for the synthesis of phenylglycine
and phenylalanine derivatives, see: (a) Katritzky, A. R.; Urogdi, L.; Mayence, A.
Synthesis 1989, 323–327.
7. (a) Le Gall, E.; Troupel, M.; Nédélec, J.-Y. Tetrahedron Lett. 2006, 47, 2497–2500;
(b) Le Gall, E.; Troupel, M.; Nedelec, J.-Y. Tetrahedron 2006, 62, 9953–9965; (c)
Sengmany, S.; Le Gall, E.; Le Jean, C.; Troupel, M.; Nédélec, J.-Y. Tetrahedron
2007, 63, 3672–3681; (d) Sengmany, S.; Le Gall, E.; Troupel, M. Synlett 2008,
1031–1035.
Scheme 2.
performs as well with phenyl bearing both electron-withdrawing
and electron-donating groups. The position of the substituent does
not influence the course of the reaction and it has to be noted that
even hindered benzyl bromides can undergo the coupling (entry
10). Furthermore, the possibility to operate with p-anisidine as
the amine provides a potential instant access to phenylalanine
derivatives by oxidative deprotection of the PMP group (entry 7).12
However, the procedure presents some limitations. A major
drawback concerns the absence of coupling between primary
amines, glyoxylate and aromatic organozinc reagents (entry 5).
This is likely due to the formation of an imine, which is not reactive
towards arylzinc reagents. This limited reactivity of non-activated
imines towards nucleophiles is a well-known issue. Another limi-
tation is the impossibility to realize three-component couplings
involving aryl bromides under Barbier-like conditions. Indeed, a
bis-amino ester resulting from the C-C reductive coupling of the
formal iminium ion under such reductive conditions (presence of
Zn dust) is the major product of the reaction (Scheme 2).
In conclusion, this work demonstrates that preformed or in situ-
generated organozinc reagents can be very convenient nucleo-
philes in three-component couplings with ethyl glyoxylate and
amines. To the best of our knowledge, this constitutes the first
example of the use of organozinc reagents in such a multicompo-
nent procedure leading to a-amino acid derivatives. The develop-
ment of an enantioselective version of the reaction is ongoing
and will be reported in due course.
8. Organozinc reagents are known to be alkaline compounds.
9. Fillon, H.; Gosmini, C.; Périchon, J. J. Am. Chem. Soc. 2003, 125, 3867–3870.
10. General procedure starting from aryl bromides: A dried 100 mL round-bottomed
flask was flushed with argon and charged with acetonitrile (40 mL). Cobalt
bromide (0.66 g, 3 mmol), zinc bromide (0.68 g, 3 mmol), phenyl bromide
(0.32 mL, 3 mmol), zinc dust (6 g, 92 mmol) and trifluoromethanesulfonic acid
(0.2 mL) were added to the solution under vigorous stirring (ca. ꢀ500 rpm).
After ca. 15 min, the aryl bromide (30 mmol) was added to the solution and as
soon as the exothermic reaction had began (ca. 5 min), a water bath at room
temperature was used to moderate the temperature of the medium. After
30 min, stirring was stopped and the surrounding solution was taken up using
a syringe and transferred into another flask containing the amine (10 mmol)
and ethyl glyoxylate (ꢀ50% solution in toluene, 2.6 mL, ꢀ13 mmol) in 10 mL
acetonitrile. After 5 min at room temperature, the mixture was heated at 50 °C
for 3–4 h using an oil bath. The reaction was then quenched with a saturated
ammonium chloride solution (150 mL) and the organic products extracted
with dichloromethane (2 Â 100 mL). After removal of the solvent,
a
chromatographic purification on neutral alumina using pentane/
a
dichloromethane mixture as an eluant (80/20?10/90) afforded the pure
product.
11. General procedure starting from benzyl bromides:
A dried 100 mL round-
bottomed flask was flushed with argon and charged with acetonitrile
(40 mL). Zinc dust (2 g, 30 mmol) and trifluoromethanesulfonic acid (0.2 mL)
were added under vigorous stirring (ca. ꢀ500 rpm). After 5 min, the amine
(10 mmol), ethyl glyoxylate (ꢀ50% solution in toluene, 2.6 mL, ꢀ13 mmol) and
the functionalized benzyl bromide (22 mmol) were added to the solution and
allowed to react for 1 h at room temperature. The reaction was quenched with
a saturated ammonium chloride solution (150 mL) and the organic products
extracted with dichloromethane (2 Â 100 mL). After removal of the solvent, a
Acknowledgement
The authors thank Dr. Jacques Royer (Université Paris Des-
cartes) for helpful discussions.
chromatographic purification on neutral alumina using
dichloromethane mixture as an eluant (80/20?10/90) afforded the pure
product. Alternatively, the pure
-amino ester could be obtained from the
a
pentane/
References and notes
a
crude oil using an acid-base work-up, as detailled in Ref. 7b.
12. (a) De Lamo Marin, S.; Martens, T.; Mioskowski, C.; Royer, J. J. Org. Chem. 2005,
70, 10592–10595; (b) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L.
M.; Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006, 47,
8109–8113.
1. For some selected examples, see: (a) Sardina, J. F.; Rapoport, H. Chem. Rev. 1996,
96, 1825–1872; (b) Rutjes, F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc.,
Perkin Trans. 1 2000, 4197–4212; (c) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002,
58, 2481–2495; (d) Kaiser, J.; Kinderman, S. S.; van Esseveldt, B. C. J.; van Delft,