First amidocarbonylation with nitriles for the synthesis of N-acyl amino acids

Article abstract of DOI:10.1055/s-1999-2524

A new and efficient one-pot synthesis of N-acyl-α-amino acids by amidocarbonylation is described. Starting from aldehydes, nitriles and carbon monoxide in the presence of acid and palladium catalysts the desired N-acyl amino acids are obtained in good yie

Full text of DOI:10.1055/s-1999-2524

108
LETTER
First Amidocarbonylation with Nitriles for the Synthesis of N-Acyl Amino
Acids1
M. Beller*, M. Eckert, W. A. Moradi
Institut für Organische Katalyseforschung an der Universität Rostock e.V., Buchbinderstraße 5-6, D-18055 Rostock, Germany
Tel.: +49-381466930; Fax +49-3814669324; E-mail: matthias.beller@ifok.uni-rostock.de
Received 17 September 1998
Abstract: A new and efficient one-pot synthesis of N-acyl-α-ami-
no acids by amidocarbonylation is described. Starting from
aldehydes, nitriles and carbon monoxide in the presence of
acid and palladium catalysts the desired N-acyl amino acids
are obtained in good yields. This new amidocarbonylation
method is attractive for industrial application and provides
an elegant route to several N-acyl amino acids via nitriles as
economically attractive amide equivalents.
Key words: amidocarbonylation, palladium, homogenous cataly-
sis, amino acids, nitriles
The synthesis of N-acyl α-amino acids is of continuous in-
terest in organic chemistry due to their exceptional bio-
chemical and medicinal importance.2 In this respect N-
acyl amino acids are an integral part of several pharma-
ceuticals,3 e.g. the hypotensive proline derivative capto-
prile and N-acetyl cysteine, an active mucolytic agent, and
constitute important subunits in new lead structures for
pharmaceuticals.4 In addition, these compounds are gen-
erally used as precursors for optically pure amino acids
and are important for the chemical industry as fine chem-
icals such as specialty detergents, and cosmetic prepara-
tions.5
While the classical route to N-acyl α-amino acids consists
of the combination of the Strecker reaction6 and subse-
quent acylation by the Schotten-Baumann-method, a
more elegant and atom efficient method is the so-called
amidocarbonylation.7 Here, in the presence of a transition
metal catalyst aldehydes react with amides and carbon
monoxide to yield the corresponding N-acyl α-amino ac-
id. Although in the past mainly cobalt-catalyzed ami-
docarbonylations have been described,8 recently
corresponding amides in high yield and selectivity under
introduced palladium catalysts show a broader substrate
amidocarbonylation reaction conditions are of interest to
tolerance and allow to perform amidocarbonylation reac-
tions under milder conditions.9
both synthetic organic and industrial chemists.
We thought that the corresponding nitriles would repre-
sent excellent starting materials for the preparation of
amides. Clearly, most simple nitriles such as acetonitrile,
benzonitrile and benzyl cyanide are less expensive com-
pared to the corresponding amides and a number of func-
tionalized nitriles are easily synthesized by simple
nucleophilic substitution reactions.
Although aldehydes and amides are in general readily
available feedstocks, there is still a need for alternative
starting materials for amidocarbonylations. While in the
past various methods were developed for the in situ gen-
eration of the aldehyde9b, 10 there is, to the best of our
knowledge, no alternative building block known which
can be used as a substitute for the amide. This is even
more surprising because the amide generally represents
the cost limiting factor of the starting materials, and only
a limited number of amides are commercially available.
Hence, inexpensive amide equivalents that generate the
Herein, we report various protocols for the amidocarbon-
ylation of nitriles using a one-pot nitrile hydrolysis and
subsequent carbonylation reaction. It is interesting to note
that the in situ generation of amides from nitriles in ami-
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LETTER
Synthesis of N-Acyl Amino Acids
109
docarbonylation reactions has not been suggested previ-
ously. This may be due to the severe alkaline or acidic
conditions used for selective nitrile hydrolysis and the
supposed sensitivity of the amidocarbonylation multi-
component reaction. However, we show here that the pal-
ladium-catalyzed amidocarbonylation reaction tolerates
several highly acidic conditions without significant de-
crease in conversion and selectivity. Our initial experi-
ments for selective nitrile hydrolysis focused on the use of
conc. sulfuric acid with one equivalent of water. This clas-
sical nitrile hydrolysis reaction11 yields almost quantita-
tively the amide. More importantly the acidic medium
does not affect adversely the palladium-catalyzed ami-
docarbonylation sequence. For the reaction sequence it is
advantageous to first add the nitrile to one equivalent of
conc. sulfuric acid and water and then add NMP, the cat-
alyst system and the aldehyde. Under CO pressure the
mixture is amidocarbonylated and after work-up the de-
sired N-acyl amino acids are obtained in good to excellent
yields (Table 1). Utilizing this one-pot procedure we
synthesized functionalized ortho-, meta-, and para-sub-
stituted N-acyl phenylglycines (1-3), N-acetyl-α-napth-
ylglycine (7) and various N-acyl derivatives of aliphatic
non-natural amino acids. Worth mentioning is the synthe- yields from nitriles, aldehydes, and formic acid consists of
sis of N-phenacetyl cyclohexylglycine (6); in this case the bubbling of HCl(g) through the mixture of formic acid
corresponding amide is not commercially available and and acetonitrile and subsequently performing the carbon-
this amide derivative enables the use of the penicillin-G- ylation (Table 2, entry 4).
acylase for enantioselective acyl hydrolysis.
In conclusion, our preliminary studies have shown that the
Although the procedure described above is easily per- combination of nitrile hydrolysis and subsequent carbon-
formed on multi gram scale and uses inexpensive starting ylation enables the use of inexpensive starting materials
materials, we sought to further improve the method by ap- for the synthesis of a variety of N-acyl amino acids.14 This
plying other in situ amide preparation protocols. Particu- one-pot procedure is particularly attractive for industrial
larly interesting is the selective hydrolysis protocol with application.
formic acid.12 From the standpoint of atom efficiency this
method is superior to the well-known nitrile hydrolysis
using conc. sulfuric acid since the formation of a stoichi-
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(Be 1931/1-1; Be 1931/2-1).Generous gifts of precious metals from
Degussa AG are gratefully acknowledged. We thank Prof. Brian E.
Hanson (Virginia State University) and Prof. K. Drauz (Degussa
AG) for valuable discussions.
ometric amount of salt is avoided. Moreover, the carbon
monoxide produced in situ from formic acid can very ele-
gantly be employed in the subsequent amidocarbonyla-
tion step. Indeed the hydrolysis of nitriles using formic
acid proceeds under a variety of conditions. The results of
the amidocarbonylation of nitriles and formic acid are
shown in Table 2. Nitriles are hydrolyzed by formic acid
at higher temperatures (200 °C). However, due to the
drastic conditions we only obtained after subsequent ami-
docarbonylation, 41 % yield of the desired N-acetyl amino
acid (Table 2, entry 1). In the literature it is known that ni-
trile hydrolysis in the presence of a catalytic amount of
hydrogen halide proceeds under milder reaction condi-
tions.13 Hence, we employed catalytic amounts both of ha-
lide ions and sulfuric acid to form the hydrogen halide in
situ as the catalyst for the hydrolysis of acetonitrile, which
was used beneficially as solvent (Table 2, entry 3). How-
ever the product yields were only moderate. Therefore, we
turned our interest to the direct use of HCl as a catalyst for
nitrile hydrolysis in the presence of formic acid and sub-
sequent amidocarbonylation. The most efficient one-pot
procedure to obtain the N-acetyl amino acid in high
References and Notes
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M. Beller et al.
LETTER
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General procedure for amidocarbonylation:
To a stirred solution of 24.5 mmol water and 25.0 mmol sul-
furic acid (98 %), 25.0 mmol nitrile was added dropwise.
After addition of the nitrile, the mixture was heated to 80 °C
and stirred for 0.5 h. After cooling to room temperature an
N-methylpyrrolidone (NMP) solution (25 ml) 1M in aldehyde,
and (PPh3)2PdBr2 (0.25 mol%), and LiBr (35 mol%) was ad-
ded. The mixture was allowed to react under 60 bar CO at
100 °C for 20 h. The volatile components were removed in
vacuo, and the residue was dissolved in a mixture of 5.0 ml 6.0
N NaOH and 20.0 ml of a saturated aqueous solution of
NaHCO3. After washing with chloroform and ethyl acetate the
aqueous phase was adjusted to pH 2 with phosphoric acid. The
precipitate was filtered off, washed with water and dried in va-
cuo. The product was recrystallized from a suitable solvent
mixture. All isolated compounds were characterized by NMR,
IR and mass spectroscopy. The purity of the products, as mea-
sured by HPLC, was > 98 %.
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Synlett 1999, No. 1, 108–110 ISSN 0936-5214 © Thieme Stuttgart · New York