Bi(OTf)3-catalyzed three-component synthesis of α-amino acid derivatives

Article abstract of DOI:10.1039/c4ob00265b

A highly efficient Bi(OTf)₃-catalyzed multicomponent synthesis of arylglycines from readily available starting materials is described. The reaction proceeds under mild conditions and provides a general route to various N-protected arylglycines. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00265b

Organic &
Biomolecular Chemistry
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Bi(OTf)3-catalyzed three-component synthesis of
α-amino acid derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 2356
Angelika E. Schneider, Tamara Beisel, Andrej Shemet and Georg Manolikakes*
Received 5th February 2014,
Accepted 18th February 2014
DOI: 10.1039/c4ob00265b
www.rsc.org/obc
A highly efficient Bi(OTf)3-catalyzed multicomponent synthesis of
arylglycines from readily available starting materials is described.
The reaction proceeds under mild conditions and provides a
general route to various N-protected arylglycines.
α-Arylglycines are interesting and important non-proteinogenic
amino acids. The α-arylglycine motif is found in many signifi-
cant drugs and natural products including glycopeptide anti-
biotics (e.g. vancomycin and teicoplanins) and the widely used
β-lactam antibiotics (e.g. norcardicins, amoxicillins and cepha-
lecins) (Fig. 1).1 Arylglycines have been shown to selectively
modulate the activity of metabotropic glutamate receptors, a
promising new approach for the treatment of neurodegenera-
tive disorders such as Parkinson’s disease.2
Due to this impressive range of biological activities, various
methods for the synthesis of arylglycine derivatives have been
developed during the last few decades.3,4 Reactions based on
the addition of a carbon nucleophile to a reactive imine- or
iminium-species,5,6 such as the Strecker reaction,7 the
Mannich reaction8 or the Petasis reaction,9 are widely used in
industry and academia. Recently, we have developed an
Scheme 1 Three-component synthesis of arylglycines.
efficient iron-catalyzed three-component synthesis of arylgly-
cines from simple starting materials (Scheme 1).10 Although
this method provides an atom-economic and cost-effective
route to arylglycines, it has some limitations. Sulfonamides or
unhindered secondary amides do not react in the presence of
an iron-catalyst and only reactions with at least moderately
electron-rich aromatic components, such as m-xylene, provide
the desired products in reasonable yields. The observed
modest catalytic activity of the employed iron(III) salts can be
rationalized by their moderate Lewis acidity.11 We anticipated
that substitution of the iron-catalyst with a stronger Lewis acid
should lead to a more general three-component reaction.
In previous studies, we had already identified Bi(OTf)3 as a
very effective catalyst for three-component amidoalkylation
reactions.12 Since Bi(OTf)3 is commercially available for a
reasonable price,13 nontoxic, air- and moisture-stable, it is a
very attractive catalyst.14–17
Fig. 1 Arylglycine moieties in biologically active molecules.
Indeed, Bi(OTf)3 could catalyze the reaction between benz-
amide, ethyl glyoxalate and m-xylene very efficiently even at low
catalyst loadings (Table 1, entries 1–4). Other Bi3+ salts or
HOTf, a possible byproduct from the hydrolysis of Bi(OTf)3,
displayed reduced catalytic activity. To exclude a possible
Department of Organic Chemistry and Chemical Biology, Goethe University
Frankfurt, Frankfurt am Main, Germany.
E-mail: g.manolikakes@chemie.uni-frankfurt.de
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00265b
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Table 1 Survey of catalystsa
Entry
Catalyst (mol%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Bi(OTf)3 (5)
Bi(OTf)3 (2)
Bi(OTf)3 (1)
Bi(OTf)3 (0.5)
BiCl3 (5)
BiBr3 (5)
HOTf (5)
84
89
88
77
72
69
49
84
52
Bi(OTf)3(5) + dbpy (10)
Bi(OTf)3 (5)c
Scheme 3 Variation of amidesa. a Isolated yields of analytically pure
products. b Reaction with 1 mol% Bi(OTf)3. c Reaction with 5 mol%
Bi(OTf)3. Mes = mesityl (2,4,6-trimethylphenyl).
a General reaction conditions: benzamide (1.0 equiv.), ethyl glyoxalate
(1.2 equiv.), m-xylene (3.0 equiv.), catalyst (x mol%), 80 °C, 18 h.
b Isolated yield of the analytically pure product. c Reaction in DCE.
high catalytic activity of Bi(OTf)3 allows reactions with less
nucleophilic arenes, such as toluene or N-protected aniline
derivatives (products 4k–m).21 In most cases the regioselectiv-
ity of the reaction is good to excellent. Only in a few cases,
for example with anisole (3c) or toluene (3k), a mixture of
regioisomers was obtained.
The reaction of various primary aryl or alkyl amides with
ethyl glyoxalate and mesitylene provided the desired products
in good to excellent yields (see Scheme 3, 5a–f). Even acid sen-
sitive functionalities such as an acrylamide (product 5c) were
well tolerated. Using carbamates as the amide component, the
corresponding N-protected arylglycines, useful building blocks
for further transformations, were obtained in 86% and 65%
yield (5g and 5h). Also, in the case of the amide component,
the high catalytic activity of Bi(OTf)3 leads to a broader sub-
strate scope and facilitates reactions with unhindered cyclic
secondary amides or carbamates (products 5i–j). Sterically
more demanding acyclic secondary amides, such as 1j, or
tert-butyl carbamate (1i) did not react under the standard
conditions.‡
Scheme 2 Variation of arenesa. a Isolated yield of analytically pure
product. b Reaction with
1 2 mol%
mol% Bi(OTf)3. c Reaction with
Bi(OTf)3. d Reaction with 5 mol% Bi(OTf)3. e Obtained as a mixture of
regioisomers; the ratio of regioisomers is given in parentheses.
To our delight, also sulfonamides are suitable amide
components (Scheme 4). Reactions with alkyl- as well as aryl-
sulfonamides furnished the desired products in good to
excellent yields (7a–e).
“hidden” catalysis18 by in situ generated Brønsted acids, we
With heteroarenes as nucleophilic compounds, lower reac-
performed the reaction in the presence of 2,6-di-tert-butyl- tion temperatures were necessary to avoid direct addition of
pyridine (dbpy), a selective proton scavenger.19 Since no the heteroarene to the aldehyde (Scheme 5). In general, better
decrease in catalytic activity was observed, we assume that a results were obtained with urethane as the amide component
Bi3+-species is the active catalyst. In general, best yields were and DCE as a solvent. Under these modified conditions,
obtained in nitromethane as a solvent (entries 1–4 and 9).
several heterocycles such as thiophenes (8a–c), N-tosylpyrrole
With the optimized conditions established, the scope of the (8d), N-tosylindole (8e) and benzofuran (8f) could be utilized
method was explored. As shown in Scheme 2, reactions with as the nucleophilic component.
electron rich arenes such as mesitylene (3b), 4-bromophenol
This method is not limited to ethyl glyoxalate as the alde-
(3n)20 or anisole (3c) and its derivatives (3d–j) furnished the hyde component. Reaction with different glyoxalates, such as
desired products in good to excellent yields (4b–i, 4n). The isopropyl or benzyl glyoxalate, furnished the desired amino
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Scheme 7 Reaction of (R)-4-methyloxazolidin-2-one (11). Isolated
yield of the analytically pure product. Mes = mesityl (2,4,6-trimethyl-
phenyl).
Scheme 4 Variation of sulfonamides. Isolated yields of analytically pure
products. Mes = mesityl (2,4,6-trimethyl-phenyl).
Scheme 8 Reaction of N-phthalyl-protected valinamide (13). Isolated
yield of the analytically pure product. Mes = mesityl (2,4,6-trimethyl-
phenyl). Pht = N-phthalyl.
used (Scheme 7). This reactivity can be rationalized by an intra-
molecular addition of the phenyl group to the formed acylimi-
nium species. Unfortunately, other chiral oxazolidiones,
derived from valine or norephedrine, did not react under the
standard conditions.
Therefore we examined reactions with chiral primary
amides derived from amino acids. The three-component reac-
tion with N-phthalyl-protected valinamide 13 afforded the
desired dipeptide 14 in high yield and moderate diastereo-
selectivity (Scheme 8).22 Since both diastereomers can be sep-
arated by simple chromatography, this reaction could be used
for an unusual synthesis of dipeptides.
Scheme 5 Variation of heteroarenesa. a Isolated yields of analytically
pure products. b Reaction in nitromethane. c Obtained as a mixture of
regioisomers; the ratio of regioisomers is given in parentheses.
Conclusions
In summary, we have developed an efficient Bi(OTf)3-catalyzed
three-component synthesis of α-amino acid derivatives from
readily available starting materials. This practical and opera-
tionally simple approach has a very broad scope and water is
generated as the only by-product. In addition, we have demon-
strated that reactions with chiral amide components proceed
with moderate diastereoselectivity. The scope of these diaster-
eoselective reactions and further asymmetric transformation
are currently being investigated in our laboratory and will be
reported in due course.
Scheme 6 Variation of alkyl glyoxalates. Isolated yields of analytically
pure products. Mes = mesityl (2,4,6-trimethyl-phenyl).
acid derivatives in 50–69% yield (Scheme 6, products 10b–c).
This reaction is quite insensitive to air or moisture and there-
fore very simple to perform. Even an aqueous solution of
Acknowledgements
glyoxylic acid could be used as an aldehyde source. In this case This work was financially supported by the Fonds der Che-
the free acid 10a could be obtained in 71% yield.
mischen Industrie (Liebig Fellowship to G. M. and A. E. S.),
In order to expand the utility of this method, we investi- the Stiftung Polytechnische Gesellschaft Frankfurt am Main
gated possible diastereoselective reactions with chiral amide (Ph.D. Fellowship to T. B.), and the Goethe University
components. To our surprise, reaction with the chiral oxazoli- (Nachwuchs im Fokus-Programm). We would like to thank
dione 11 yielded the cyclic amino acid 12 as a single product, Prof. Michael Göbel (Goethe University Frankfurt) for
even if an excess of the nucleophilic arene component 3b was his support and Rockwood Lithium (Frankfurt), BASF
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(Ludwigshafen) and Evonik Industries (Darmstadt) for the
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‡General procedure for reactions with ethyl glyoxalate: A 10 mL screw-cap vial
was charged with Bi(OTf)3 (1–5 mol%), amide (1.0 equiv.), and nitromethane
(2 mL mmol−1 amide). Ethyl glyoxalate (1.2 equiv.) in nitromethane (2 mL
mmol−1 amide) and the aromatic compound (3.0–4.0 equiv.) were added under
vigorous stirring. The mixture was heated to 60–100 °C and stirred at this temp-
erature for 16 h. After cooling to room temperature, the reaction mixture was
diluted with EtOAc and filtered through a short plug of Celite. The plug was
rinsed with additional EtOAc. The combined filtrates were concentrated under
reduced pressure. Purification of the crude residue by column chromatography
(hexane–EtOAc) afforded the analytically pure product.
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