A Straightforward Three-Component Synthesis of α-Amino Esters Containing a Phenylalanine or a Phenylglycine Scaffold

Article abstract of DOI:10.1021/jo1002328

A range of α-amino esters has been synthesized in good to high yields 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 esters bearing a phenylglycine or a phenylalanine scaffold.

Full text of DOI:10.1021/jo1002328

pubs.acs.org/joc
A Straightforward Three-Component Synthesis of r-Amino Esters
Containing a Phenylalanine or a Phenylglycine Scaffold
ꢀ
Caroline Haurena, Erwan Le Gall,* Stephane Sengmany, Thierry Martens, and
Michel Troupel
ꢀ
Electrochimie et Synthese Organique, Institut de Chimie et des Materiaux Paris Est (ICMPE), UMR 7182
ꢁ
CNRS, Universiteꢀ Paris Est Creꢀteil Val-de-Marne, 2-8 rue Henri Dunant, 94320 Thiais, France
ꢀ
legall@glvt-cnrs.fr
Received February 11, 2010
A range of R-amino esters has been synthesized in good to high yields 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 esters bearing a phenylglycine or a phenylalanine scaffold.
Introduction
of peptides and as chiral pools in multistep synthesis but
also represent valuable chiral organocatalysts or attractive
building blocks in drug discovery.1 Consequently, the develop-
ment of efficient methods for the synthesis of novel nonprotei-
nogenic or unnatural R-amino acids has been a field of
extensive research over the past few years.2
R-Amino acids constitute one of the most important
families of natural products that play central roles both as
structural units of proteins and as intermediates in metabo-
lism. They are continuously employed in the elaboration
Although numerous methods allow the efficient prepara-
tion of a large range of R-amino acids derivatives, only a
limited set of processes employing multicomponent proce-
dures have been disclosed to date.3 For instance, the Petasis
three-component reaction4 among boronic acids, amines,
and glyoxylic acid has been employed for the diastereoselec-
tive synthesis of pyrrolidine-derived arylglycines5 or a
(1) For some selectedexamples, 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, 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. (f) List, B. Tetrahedron 2002, 58, 5573–
5590. (g) Hicks, R. P.; Bhonsle, J. B.; Venugopal, D.; Koser, B. W.; Magill,
A. J. J. Med. Chem. 2007, 50, 3026–3036. (h) Wang, J. Y.; Xie, J. M.; Schultz,
P. G. J. Am. Chem. Soc. 2006, 128, 8738–8739. (i) Jain, R.; Chawrai, S. Mini-
Rev. Med. Chem. 2005, 5, 469–477.
(2) (a) Williams, R. M. Synthesis of Optically Active Amino Acids; Pergamon
Press, Oxford University Press: New York, 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.
(f) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584–4671. (g) Perdih, A.;
Dolenc, M. S. Curr. Org. Chem. 2007, 11, 801–832. (h) O'Donnell, M. J. Acc.
Chem. Res. 2004, 37, 506–517. (i) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004,
37, 518–525. (j) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028. (k)
Katritzky, A. R.; Urogdi, L.; Mayence, A. Synthesis 1989, 323–327. (l) Lee, E. C.;
Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066–12067. (m) Shang, G.; Yang, Q.;
Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360–6362. (n) Williams, R. M.;
Hendrix, J. A. Chem. Rev. 1992, 92, 889–917. (o) Cordova, A.; Notz, W.; Zhong,
G.; Betancort, J. M.; Barbas, C. F. J. Am. Chem. Soc. 2002, 124, 1866–1867. (p)
Sakai, N.; Asano, J.; Kawada, Y.; Konakahara, T. Eur. J. Org. Chem. 2009, 917–
922. (q) Hirner, S.; Somfai, P. J. Org. Chem. 2009, 74, 7798–7803. (r) Lee, E. C.;
Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066–12067. (s) Shang, G.; Yang, Q.;
Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360–6362.
(3) Besides the Petasis or the Ugi reaction, the Strecker reaction might be
relevant for the synthesis of R-amino acids through preliminary preparation
of R-aminonitriles. For some exemples, see: (a) Strecker, A. Justus Liebigs
ꢀ
Ann. Chem. 1850, 75, 27–51. (b) Martınez, R.; Ramon, D. J.; Yus, M.
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Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762–766. (d)
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Baeza, A.; Najera, C.; Sansano, J. M. Synthesis 2007, 1230–1234. (e) Yadav,
J. S.; Reddy, B. V. S.; Eeshwaraiah, B.; Srinivas, M. Tetrahedron 2004, 60,
1767–1771. (f) Prakash, G. K. S.; Mathew, T.; Panja, C.; Alconcel, S.;
Vaghoo, H.; Do, C.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A. 1997, 104,
3703–3706.
(4) (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.
(5) Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46, 2025–2028.
DOI: 10.1021/jo1002328
r
Published on Web 03/21/2010
J. Org. Chem. 2010, 75, 2645–2650 2645
2010 American Chemical Society

Haurena et al.
JOCArticle
one-pot sequential R-amino ester formation and palladium-
catalyzed cyclization process.6 Isocyanide-based reactions
like the Ugi 3-CR7 have also been employed as an efficient
tool for the synthesis of leading drugs like the antiplatelet
agent clopidogrel.8 However, while these methods afford a
very convenient access to a variety of R-amino acids, none of
them allows a fast and direct entry to R-amino esters and
particularly those derived from phenylalanine.9
Over the past few years, our group has developed a
multicomponent procedure allowing the efficient formation
of R-branched amines starting from amines, aldehydes, and
preformed or in situ generated organozinc reagents.10 In a
very recent paper, we also disclosed preliminary results
regarding the use of ethyl glyoxylate as the carbonyl deriva-
tive to afford an instant access to R-amino esters.11 Herein,
we both confirm the possible use of ethyl glyoxylate as a
convenient building block of R-amino esters and further
broaden the scope of the procedure by showing its relevance
for the formation of a larger range of R-amino esters bearing
a phenylalanine or a phenylglycine moiety.
Most general and efficient reaction conditions were defined
as follows: acetonitrile is used as the solvent, zinc dust is used
as the reductive metal, and the organic bromide (2.5 equiv13),
the amine (1 equiv), and ethyl glyoxylate (1.3 equiv) are
allowed to react at room temperature.14 Under these condi-
tions, reactions generally seemed to go to completion in less
than 1 h. The results are presented in Table 1.
It appears that most benzyl bromides react quickly and
efficiently with ethyl glyoxylate and a variety of amines,
whatever the position of the functionality of the phenyl ring,
and it is noteworthy that hindered benzyl bromides can also
undergo the coupling (Table 1, entry 11). Another interesting
result concerns the opportunity of operating with p-anisidine
as the amine thus providing a potential access to proteino-
genic phenylalanine derivatives by further oxidative depro-
tection of the p-methoxyphenyl (PMP) group (Table 1, entry
15).15 It can also be mentioned that the reaction involving a
N-substituted piperazine as the amine provides a slightly
lower yield of the coupling product (Table 1, entry 3).16
In a second part of the study, we focused our research
on the synthesis of arylglycines by using aromatic bromides
in the process. Unfortunately, reactions with these halides
were at once much more complicated to achieve because a
cobalt catalyst is required during the arylzinc synthesis
step, and Barbier-like conditions are not applicable. Indeed,
under these latter conditions, it could be observed the
major formation of a bis-amino ester resulting from the
C-C reductive coupling of a formal iminium ion, in situ
generated upon reaction between the amine and the aldehyde
(Scheme 2).
Results and Discussion
As a starting point of the study, we envisaged to extend the
procedure described in our previous works devoted to the
multicomponent coupling of organozinc reagents with aro-
matic aldehydes and secondary amines to the synthesis of
R-amino esters. In this purpose, it was simply proposed to
replace the aldehyde by a non acidic glyoxylic acid equiva-
lent12 under its ethyl ester form (Scheme 1).
SCHEME 1. Principle of the Three-Component Reaction
SCHEME 2. Attempted Three-Component Coupling Involving
an Aryl Bromide under Barbier-like Conditions
In a first set of experiments, we turned our attention to the
synthesis of arylalanines. To this end, we envisaged to
explore the reactivity of benzyl bromides in three-component
couplings with amines and ethyl glyoxylate. Preliminary
results indicated that these halides can be easily in situ
metalated using zinc dust to afford coupling products in
excellent yields. Consequently, we chose to simplify the
process by operating under these Barbier-like conditions.
The formation of such compounds was also noticed, in
some limited cases, when starting from benzyl bromides.
However, only limited amounts could be detected in the
reaction medium. This accounts for a competitive formation
of the bis-amino ester and the three-component coupling
product, and we assume that such a competition occurs in
each case. Following this postulate, the fate of the reaction
might clearly depend on the ease of formation of the orga-
nozinc reagent. Consequently, if the metalation of the or-
ganic halide is too slow, the reaction might lead to the major
(6) Grigg, R.; Sridharan, V.; Thayaparan, A. Tetrahedron Lett. 2003, 44,
9017–9019.
€
(7) (a) Ugi, I.; Meyer, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
1959, 71, 386–388. (b) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8–21. (c)
€
€
Domling, A.; Ugi, I. Angew. Chem. 2000, 112, 3300–3344. (d) Domling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
(8) Kalinski, C.; Lemoine, H.; Schmidt, J.; Burdack, C.; Kolb, J.;
Umkehrer, M.; Ross, G. Synthesis 2008, 4007–4011.
(9) The Petasis reaction leads to R-amino acids with high yields. However,
reaction times are generally important, and the reaction does not tolerate the
presence of some electron-withdrawing groups connected to phenyl moieties.
The Ugi reaction requires the use of cleavable isocyanides and a further
hydrolysis step.
(13) It was mentioned in previous works that at least 2 equiv of the
organozinc compound are required for the reaction to proceed efficiently.
(14) Although an exothermic reaction tends to develop, the temperature
of the medium was not controlled. As a consequence, this rise of the medium
temperature is sufficient to avoid a preliminary heating of ethyl glyoxylate
(which is generally known to require a depolymerization step prior to use).
(15) (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.
ꢀ ꢀ
(10) (a) Le Gall, E.; Troupel, M.; Nedelec, 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.;
ꢀ ꢀ
Nedelec, J.-Y. Tetrahedron 2007, 63, 3672–3681. (d) Sengmany, S.; Le Gall,
E.; Troupel, M. Synlett 2008, 1031–1035. (e) Le Gall, E.; Haurena, C.;
Sengmany, S.; Martens, T.; Troupel, M. J. Org. Chem. 2009, 74, 7970–7973.
(11) Haurena, C.; Sengmany, S.; Huguen, P.; Le Gall, E.; Martens, T.;
Troupel, M. Tetrahedron Lett. 2008, 49, 7121–7123.
(16) Piperazine derivatives generally furnish coupling products in lower
yields. This behavior has already been observed in other studies conducted in
our laboratory.
(12) Organozinc reagents are alkaline compounds.
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TABLE 1. Three-Component Coupling between Benzyl Bromides, Amines, and Ethyl Glyoxylatea
aExperiments were typically conducted with 40 mL of acetonitrile, 25 mmol of the benzyl bromide, 2.6 mL (13 mmol) of ethyl glyoxylate in toluene,
10 mmol of the amine, and 2 g (30 mmol) of zinc dust.
formation of the reductive coupling product. Considering
that benzyl halides form organozinc reagents much more
easily than aromatic bromides, they lead to the major for-
mation of the three-component coupling product whereas
aryl bromides do not.
preformed aromatic organozinc reagents. Thus, arylzinc
reagents (>2 equiv) were generated in acetonitrile from aryl
bromides using zinc dust and cobalt catalysis17 and allowed
to react with secondary amines (1 equiv) and ethyl glyoxylate
(1.3 equiv). Results were generally unsatisfactory with only
moderate conversion of the substrates into the expected R-
amino esters, even after several hours at room temperature.
We then envisaged optimizing the procedure and examined
the influence of a set of parameters like the temperature of
the medium, the amounts of reagents or the presence, during
the coupling step, of additional salts like ZnCl2, CeCl3, CuI,
With this limitation of the procedure in mind, we decided
to realize some other preliminary experiments starting from
ꢀ
(17) (a) Fillon, H.; Gosmini, C.; Perichon, J. J. Am. Chem. Soc. 2003, 125,
ꢀ
3867–3870. (b) Kazmierski, I.; Gosmini, C.; Paris, J. -M.; Perichon, J.
Tetrahedron Lett. 2003, 44, 6417–6420. (c) Gosmini, C.; Amatore, M.;
ꢀ
Claudel, S.; Perichon, J. Synlett 2005, 2171–2174.
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TABLE 2. Three-Component Coupling between Arylzinc Reagents, Secondary Amines, and Ethyl Glyoxylatea
aExperiments were typically conducted with 25 mL of acetonitrile, ∼15 mmol of the arylzinc bromide (preformed from 20 mmol of the corresponding
aryl bromide), 2.6 mL (13 mmol) of ethyl glyoxylate in toluene, and 5 mmol of the amine. bCobalt bromide 0.55 g (2.5 mmol) was added before coupling.
cTo the filtered organozinc solution was added the amine and ethyl glyoxylate.
2648 J. Org. Chem. Vol. 75, No. 8, 2010

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AlCl3, etc. over the reaction efficiency. These experiments,
which were carried out using piperidine as a model amine,
indicated that the temperature and the amount of ethyl
glyoxylate are the most important reaction parameters.
Thus, we could observe that the rise of the amount of ethyl
glyoxylate has a general positive influence on the reaction
efficiency, whatever the nature of the function connected to
the phenyl moiety. The rise in temperature generally favors
the three-component coupling except in the case of elec-
tron-rich arylzinc compounds for which the direct addition
onto ethyl glyoxylate furnishing an alcohol rises upon
heating, in particular when the glyoxylate is used in large
excess. This is likely the consequence of a probable in-
creased nucleophilicity compared to electron-deficient ar-
ylzinc reagents. For these latter compounds, it should be
noted that the presence of an additional amount of cobalt
bromide during the coupling step can promote the three-
component reaction. This effect was observed in the parti-
cular case of an electron-deficient arylzinc reagent like 4-
ethoxycarbonylphenylzinc bromide, which gave rise to the
formation of the corresponding R-amino ester in almost
quantitative yield (see below, Table 2, entry 5). This is not
the case with electron-rich arylzinc reagents for which a
further cobalt bromide addition tends again to afford
mainly the benzhydryl alcohol. This unusual role of cobalt
bromide was not explained so far.
In the following part of the study, we endeavored to take
these indications into account to carry out three-component
reactions between secondary amines, ethyl glyoxylate, and a
range of preformed arylzinc reagents. A general procedure
could be defined as follows: acetonitrile is used as the solvent,
and the preformed arylzinc bromide (>2 equiv), the amine (1
equiv), and ethyl glyoxylate (2.6 equiv) are allowed to react
for 1 h at room temperature or under moderate heating. The
results are reported in Table 2.
These results indicate that an important range of functio-
nalized arylzinc compounds and secondary amines is usable
in the three-component reaction, providing an instant access
to a variety of R-amino esters derivatives. In most cases,
heating was not necessary, and reactions were conducted at
room temperature. However, in agreement with the preli-
minary experiments discussed above, very satisfactory yields
could be obtained from electron-deficient organozinc re-
agents provided that moderate heat is applied to the reaction
medium (Table 2, entries 5, 6, 10, and 11).
FIGURE 1. Plausible reaction pathways.
Reaction Mechanism
The reaction mechanism remains unclear. Some works
indicate that Bruylants-type reactions of R-aminonitri-
les are achievable using organozinc reagents as nucleo-
philes.19 This suggests that these compounds constitute
very convenient nucleophiles for addition onto iminium
salts. Another possible mechanism is proposed by Fan and
co-workers in a recent study dealing with the multicompo-
nent reaction of allyl and benzylzinc halides, aldehydes,
and primary amines.20 It is mentioned that the imine,
which is formed upon reaction between the amine and
the aldehyde, is not the reactive electrophile of the process.
It is suggested that the hemiaminal which is formed during
the course of the reaction is deprotonated by the organo-
zinc compound and that the resulting zinc alcoholate is
subsequently engaged in a putative six-membered transi-
tion-state with a second equivalent of the organozinc to
finally give rise to the formation of the three-component
coupling product.
Both plausible reaction pathways are depicted in Figure 1.
Actually, we assume that the reaction pathway might not
be univocal. Indeed, it was noticed that in close relationship
with the aromatic or the benzylic nature of the organome-
tallic, different amounts of ethyl glyoxylate are required for
the reaction to proceed efficiently. We could also make the
experimental observation that in situ metalations can be
carried out only starting from benzyl bromides. These latter
compounds are also able to react with aldehydes and primary
amines whereas arylzinc compounds can not. Taken to-
gether, these results could simply indicate a significant
difference of nucleophilicity between both organozinc spe-
cies. However, this could also account for different reaction
pathways, depending on the nature of the organic halide.
Some further investigations dedicated to the comprehension
of the reaction mechanism are currently in progress in the
laboratory.
Although the results reported herein provide representa-
tive examples of straightforward amino esters synthesis, the
procedure suffers another drawback. As reported in a pre-
vious paper,11 a limitation concerns the absence of three-
component coupling when primary amines are used in the
presence of aldehydes and aromatic organozinc reagents.
This is likely due to the formation of imines whose limited
reactivity toward nucleophiles is a well-known issue which
might be overcome, for instance, by activation of the CdN
bond under an acyliminium ion form.18
(18) For a review of additions to N-acyliminium ions, see: Speckamp, W.
N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856. For recent examples,
see: (a) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497–1499. (b) Black,
D. A.; Arndtsen, B. A. J. Org. Chem. 2005, 70, 5133–5138. (c) Wei, C.; Li,
C. -J. Lett. Org. Chem. 2005, 2, 410–414. (d) Black, D. A.; Arndtsen, B. A.
Tetrahedron 2005, 61, 11317–11321. (e) Black, D. A.; Arndtsen, B. A. Org.
Lett. 2006, 8, 1991–1993. (f) Zhang; Malinakova C. J. Org. Chem. 2007, 72,
1484–1487.
(19) (a) Le Gall, E.; Gosmini, C.; Troupel, M. Tetrahedron Lett. 2006, 47,
455–458. (b) Moumne, R.; Lavielle, S.; Karoyan, P. J. Org. Chem. 2006, 71,
3332–3334. (c) Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Fochi, M.;
Comes-Franchini, M.; Ricci, A. Synlett 2003, 1778–1782.
(20) Fan, R.; Pu, L.; Qin, L.; Wen, F.; Yao, G.; Wu, J. J. Org. Chem. 2007,
72, 3149–3151.
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Conclusion
for 15 min. The aryl bromide (20 mmol) and cobalt bromide
(0.44 g, 2 mmol) were added to the mixture, and after 30 min at
room temperature, stirring was stopped and the surrounding
solution was taken up using a syringe and transferred into
another flask containing the amine (5 mmol) and ethyl glyoxy-
late (∼50% solution in toluene, 2.6 mL, ∼13 mmol, depolymer-
ized prior to use by 30 min heating at 60 °C) in 10 mL of
acetonitrile. After 1 h at room temperature, the reaction
was quenched with a saturated ammonium chloride solution
(100 mL), and the organic products were extracted with dichlor-
omethane (2 ꢀ 100 mL). After removal of the solvent, a chro-
matographic purification on neutral alumina using a pentane/
diethyl ether mixture as an eluant (90/10 f 10/90) afforded the
pure product. Alternatively, the pure R-amino ester could be
obtained from the crude oil using an acid-base workup, as
detailed in ref 10b.
In conclusion, we have demonstrated that non-natural R-
aminoesters derived from phenylalanine and phenylglycine
can be successfully obtained through a simple and efficient
three-component reaction between ethyl glyoxylate, amines,
and organozinc reagents. We could show that, while the
formation of arylglycines has to be undergone starting from
preformed arylzinc reagents, the synthesis of arylalanines can
be realized in a single experimental step involving the in situ
metalation of benzyl bromides and their subsequent three-
component reaction with an amine and ethyl glyoxylate.
Consequently, we found a reliable reaction system, able to
provide an important variety of R-amino ester backbones in
very useful reaction conditions, further making this strategy
relevant for parallel synthesis. The extension of the process to
cleavable amines, used as chiral auxiliaries, as well as the
development of a chiral catalytic version of the reaction are
currently under progress and will be reported in due course.
Characterization Data for Compound 1a. Obtained through
typical procedure A as a colorless oil. m = 2.48 g (95%). ATR-
FTIR (neat, cm-1): 2933, 1726, 1184, 1148, 1115, 1053, 747, 698.
1H NMR (400 MHz): δ 7.29-7.18 (m, 5H), 4.11-4.03 (m, 2H),
3.41 (dd, J = 9.8, J = 5.5 Hz, 1H), 3.11-2.94 (m, 2H), 2.77-
Experimental Section
2.49 (m, 4H), 1.68-1.42 (m, 6H), 1.15 (t, J = 7.1 Hz, 3H). 13
C
NMR (100 MHz): δ 171.4, 138.4, 129.3, 128.2, 126.3, 70.4, 59.9,
51.1, 35.9, 26.5, 24.6, 14.4. MS m/z (relative intensity): 188 ([M -
CO2Et]þ,79), 170 ([M - PhCH2]þ,100), 142 (37), 124 (5), 105
(15), 96 (6). HRMS: calcd for C16H24NO2 [M þ H]þ 262.1807,
found 262.1815.
Characterization Data for Compound 2a. Obtained through
typical procedure (B) as a yellow oil. m = 0.86 g (62%). ATR-
FTIR (neat, cm-1): 2633, 1731, 1610, 1510, 1245, 1151, 1067,
835. 1H NMR (400 MHz): δ 7.28 (d, J = 8.7 Hz, 2H), 6.79 (d,
J = 8.7 Hz, 2H), 4.16-4.00 (m, 2H), 3.81 (s, 1H), 3.73 (s, 3H),
2.45-2.20 (m, 4H), 1.55-1.47 (m, 4H), 1.38-1.32 (m, 2H), 1.13
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz): δ 172.1, 159.5, 130.0,
128.3, 113.8, 74.4, 60.7, 55.3, 52.4, 25.8, 24.4, 14.2. MS m/z
(relative intensity): 204 ([M - CO2Et]þ, 100), 136 (5), 121 (59).
HRMS: calcd for C16H24NO3 [M þ H]þ 278.1756, found
278.1745.
Typical Procedure from Benzyl Bromides (A). A dried 100 mL
round-bottomed flask was flushed with argon and charged with
acetonitrile (40 mL). Zinc dust (2 g, 30 mmol) and trifluoroacetic
acid (0.2 mL) were added under vigorous stirring. After 5 min,
the amine (10 mmol), ethyl glyoxylate (∼50% solution in
toluene, 2.6 mL, ∼13 mmol), and the benzyl bromide (25 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 pro-
ducts were extracted with dichloromethane (2 ꢀ 100 mL). After
removal of the solvent, a chromatographic purification on
neutral alumina using a pentane/diethyl ether mixture as an
eluant (90/10f10/90) afforded the pure product. Alternatively,
the pure R-amino ester could be obtained from the crude oil
using an acid-base workup, as detailed in ref 10b.
Typical Procedure from Aryl Bromides (B). A dried 100 mL
round-bottomed flask was flushed with argon and charged with
acetonitrile (25 mL). Zinc dust (4 g, 61 mmol), trifluoroacetic
acid (0.2 mL), and 1,2-dibromoethane (0.3 mL) were added, and
the solution was heated under vigorous stirring until gas was
evolved. Heating was stopped and the solution allowed to cool
Supporting Information Available: Full experimental pro-
cedures, characterization data, and copies of NMR spectra for
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
2650 J. Org. Chem. Vol. 75, No. 8, 2010