Synthesis of N-Acetyl-α-aminobutyric Acid via Amidocarbonylation: A Case Study

Article abstract of DOI:10.1002/adsc.200390059

The synthesis of N-acetyl-α-aminobutyric acid by amidocarbonylation of propionaldehyde with acetamide in the presence of palladium catalysts is studied in detail. The influence of various reaction conditions and compositions (e.g., the co-catalysts acid and bromide) on the yield of N-acetyl-α-aminobutyric acid is shown. For the first time it is demonstrated that the palladium-catalyzed amidocarbonylations of aldehydes can be run with significantly lower halide concentrations (<30 mol %) without a major yield decrease. While phosphine-free catalyst systems give best yields at low CO pressure, phosphine-ligated palladium catalysts lead to better yields at higher CO pressure. At low palladium loadings (<0.1 mol %), unwanted condensation reactions of propionaldehyde become increasingly competitive.

Full text of DOI:10.1002/adsc.200390059

FULL PAPERS
Synthesis of N-Acetyl-a-aminobutyric Acid via
Amidocarbonylation: A Case Study
Dirk Gˆrdes,a Helfried Neumann,a Axel Jacobi von Wangelin,a Christine Fischer,a
Karlheinz Drauz,b Hans-Peter Krimmer,b Matthias Bellera,*
a
Institut f¸r Organische Katalyseforschung an der Universit‰t Rostock e.V., Buchbinderstr. 5 6, 18055 Rostock, Germany
Fax: ( ‡ 49)-381-4669-324, e-mail: matthias.beller@ifok.uni-rostock.de
b
Technologie- und F&E-Management, Degussa Feinchemie, 63457 Hanau, Germany
Fax: ( ‡ 49)-61-8159-3930, e-mail: karlheinz.drauz@degussa.com
Received: November 5, 2002; Accepted: December 4, 2002
Abstract: The synthesis of N-acetyl-a-aminobutyric major yield decrease. While phosphine-free catalyst
acid by amidocarbonylation of propionaldehyde with systems give best yields at low CO pressure, phos-
acetamide in the presence of palladium catalysts is phine-ligated palladium catalysts lead to better yields
studied in detail. The influence of various reaction at higher CO pressure. At low palladium loadings
conditions and compositions (e.g., the co-catalysts (<0.1 mol %), unwanted condensation reactions of
acid and bromide) on the yield of N-acetyl-a-amino- propionaldehyde become increasingly competitive.
butyric acid is shown. For the first time it is
demonstrated that the palladium-catalyzed amidocar-
bonylations of aldehydes can be run with significantly Keywords: N-acetyl-a-aminobutyric acid; amidocar-
lower halide concentrations (<30 mol %) without a bonylation; amino acids; catalysis; palladium
Introduction
chiometric amounts of salts, requires a great deal of
improvement.
The synthesis of N-acyl-a-amino acids has aroused
A promising direct (™one-pot∫) route to racemic N-
continuous attention because of their exceptional bio- acyl-a-amino acids 1 is the so-called amidocarbonyla-
chemical importance as integral part of peptides and tion reaction, which comprises the reaction of an
proteins.[1] In addition, N-acyl-a-amino acids constitute aldehyde, an amide, and carbon monoxide in the
interesting building blocks for organic synthesis and are presence of cobalt or palladium catalysts (Scheme 1).[7]
of commercial importance as industrial fine chemicals.[2] In view of modern economic and environmental con-
A wide spectrum of industrial applications of N-acyl-a- cerns, the remarkable features of the amidocarbonyla-
amino acids is based on their biological activity as small- tion are 100% atom efficiency and the utilization of
molecule drugs. Here, captopril, a hypotensive proline ubiquitous and cheap starting materials.
derivative,[3] and N-acetylcysteine, an active mucolytic
The amidocarbonylation reaction was accidentally
discovered by H. Wakamatsu at Ajinomoto Co. in 1970
agent,[4] are two of the most prominent examples.
The paramount importance of various N-acylamino while studying the oxo process of acrylonitrile with
acids has attracted considerable interest in industrial- Co2(CO)8 as catalyst.[8] Some time ago, we developed
scale productions. Apart from fermentation of natural highly efficient palladium catalyst systems for this
amino acids and subsequent acylation, a large number of reaction. Stimulated by a few initial experiments of
elegant synthetic routes to non-natural amino acids have J‰gers,[9] we demonstrated for the first time that
been developed in recent decades.[5] However, most of aliphatic and aromatic aldehydes smoothly react with
these reactions are not suited for an economic multi-kg various amides and CO in the presence of palladium/
preparation. Still, the classical Strecker and Bucherer
Bergs reactions in combination with subsequent hydrol-
ysis are the benchmarks for the industrial synthesis of
non-natural amino acids. The sequence of Strecker
reaction and subsequent acylation is established on
large scale by Tanabe and Degussa.[6] From a stand-
point of sustainability, this three-step synthesis
phosphine catalysts and acid co-catalyst to give a variety
O
O
R1
O
[Pd], CO,
+
R1
R2
NH2
R2
N
H
CO2H
H
LiBr, H2SO4
1
Scheme 1. Pd-catalyzed amidocarbonylation of aldehydes
(Strecker, hydrolysis, acylation), which generates stoi- with amides.
510
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/03/34504-510 516 $ 17.50-.50/0
Adv. Synth. Catal. 2003, 345, No. 4

Synthesis of N-Acetyl-a-aminobutyric Acid via Amidocarbonylation
FULL PAPERS
O
O
O
O
O
[Pd], CO
H
+
NH2
NH2
NH2
N
H
CO2H
H
LiBr, H2SO4, NMP
N
N
O
O
2
4
3
Scheme 2. Pd-catalyzed amidocarbonylation of propionalde-
hyde with acetamide.
Figure 1. (À)-(S)-a-Ethyl-2-oxo-1-pyrrolidine-acetamide
¾
¾
(Levetiracetam ) (3) and the structurally related Piracetam
(4).
O
O
O
HN R2
HN R2
R1
R1
H2N R2
+
H
H2O
O
O
6
H2N R2
OH O
R1
N
H
R2
H2O
HX
5
H
SN2
H2O
R1
O
N
R2
R2
R2
H
H
7
X
O
O
R1
N
H
R2
R1
N
H
R2
8
O
R
N
H
SN1
X
O
X
R1
N
H
Scheme 3. Proposed pre-equilibria for the Pd-catalyzed ami-
docarbonylation.
Figure 2. Six-fold parallel autoclave with aluminum insert
and glass reaction tubes.
reaction set-ups, we performed most of the reactions in a
parallel manner to ensure identical reaction conditions
of N-acyl-a-amino acids.[10] In addition to carboxamides, and generally enhance the throughput (Figure 2).[16]
ureas were also shown to undergo a similar reaction
(ureidocarbonylation) to give the corresponding hydan-
toins.[11]
Results and Discussion
More recently, we became interested in the synthesis
of N-acetyl-a-aminobutyric acid (2) which is used as an Initial experiments (Scheme 2) were run under the
ingredient in skin disease drugs.[12] The amidocarbony- conditions previously optimized for other aliphatic
lation of propionaldehyde and acetamide clearly repre- aldehydes. Due to the increased reactivity of propion-
sents the economically most attractive route to this aldehyde in unwanted aldol reactions, a larger excess
target molecule with special regard to raw material costs of the aldehyde (200 mol %) was used compared to
and number of reaction steps. Apart from N-acetyl-a- the standard amidocarbonylation conditions (100
aminobutyric acid (2) , the deacylatedamino acid itself is mol %).[17]
even more important as it is a component of some
The proposed mechanism of the underlying domino
proteins, albeit in extremely small amounts. The most condensation-carbonylation-hydrolysis sequence is
significant pharmaceutical application for a-aminobu- shown in Schemes 3 and 4. Aldehyde and amide
tyric acid is the use for the preparation of Levetirace- combine to give N-(a-hydroxyalkyl)amide 5, which is
¾
tam (3) (Figure 1).[13]
in equilibrium with other condensation products, such as
¾
Levetiracetam (3) is a relatively new anti-epileptic 1,1-bisamide 6, N-acylimine 7, and N-acylenamine
drug,[14]] which was released in November 2000 and is species. In the presence of catalytic bromide ions, a
structurally related to well-known Piracetam (4).[15]
small amount of the N-(a-bromoalkyl)amide 8 is
¾
In this paper, we present an in-depth study of the formed. We assume that a catalytically active Pd(0)
palladium-catalyzed amidocarbonylation of propional- species, which arises from the employed Pd(II) precur-
dehyde which is of general interest for the production of sor under the predominantly reductive reaction con-
a-aminobutyric acid derivatives. We examined the ditions (CO, aldehyde, phosphine), subsequently inserts
influence of wide variations of the reaction conditions into the alkyl C-Br bond via oxidative addition
and compositions on the outcome of the amidocarbo- (Scheme 4). Similar palladium-catalyzed activation
nylation of propionaldehyde with acetamide and CO. In processes of alkyl bromides and chlorides have been
order to cut down time- and cost-extensive solitary recently reported by Knochel,[18] Fu,[19] and us.[20]
Adv. Synth. Catal. 2003, 345, 510 516
511

Dirk Gˆrdes et al.
FULL PAPERS
X
The resultant palladium(II) alkyl complex 9 is trans-
formed to the corresponding acyl complex 10 by intra-
molecular CO insertion. Upon hydrolytic cleavage, the
desired N-acetyl-a-amino acid is released and the
catalytically active Pd(0) species is recycled. Although
the intermolecular attack by water might be the most
likely cleavage pathway, the intermediacy of an oxazo-
lone 11 cannot be excluded.
L
Pd
O
L
R1
N
H
R2
X
O
9
CO
R1
N
H
R2
PdL2
8
L
X
Pd
R1
O
O
L
N
H
R2
– HX
10
Initially, the influence of the crucial reaction param-
eters pressure and temperature using PdBr2/PPh3 and
PdBr2 as catalyst systems was studied in our test
reaction. Under the standard conditions, the phos-
phine-free catalyst generally gave higher yields of N-
acetyl-a-aminobutyric acid than the phosphine-ligated
catalyst system (Figure 3). This demonstrates that
phosphine ligands mainly have a stabilizing effect on
the metal complex in this reaction but do not increase
the activity. Amidocarbonylation reactions are usually
associated with temperatures above 60 8C. At lower
temperatures, the predominant formation of 1,1-bis-
amidopropane 12 and other unwanted aldol condensa-
tion products was observed. So far, the best results
(>80%) were obtained at 100 8C in the presence of
PdBr2. At temperatures > 120 8C, a significant decrease
in the product yield was observed, mostly due to the
rapid consumption of propionaldehyde in aldol reac-
tions.
O
O
R2
X
O
N
R1
O
11
R1
N
H
R2
H2O
OH
O
H2O
O
R1
N
H
R2
1
Scheme 4. Proposed mechanism for the palladium-catalyzed
carbonylation.
Studies of the influence of the CO pressure on the
palladium-catalyzed amidocarbonylation of aldehydes
have largely been neglected in the past. Generally,
reactions were performed at (somewhat arbitrary) 60
bar CO pressure. In order to provide a concise study, the
test system propionaldehyde/acetamide was subjected
to wide variations of the CO pressure (10 120 bar,
Figure 4). Reactions with the phosphine-free reference
system (PdBr2) were studied at 100 8C, whereas reac-
tions with the PdBr2/PPh3 system were performed at 80,
100, and 120 8C. Surprisingly, the CO pressure revealed
a major influence on the overall yield. As shown in
Figure 4, only low yields (10 30%) were detected at 20
bar. With PdBr2 as catalyst, the reaction proved rather
independent of the applied pressure above 40 bar.
However, in the presence of triphenylphosphine, the
yield increased as the CO pressure was increased.
Especially at elevated temperatures (100 and 120 8C),
an increased CO pressure (80 120 bar) was observed to
have a remarkably enhancing effect on the yield.
Apparently, high-pressure conditions are needed to
ensure rapid CO insertion in the presence of PPh3
ligand. Hence, one could conclude that CO and the
phosphine act as competing ligands. While the former
drives the product formation, the latter somewhat
inhibits product formation but is likely to exhibit a
stabilizing effect on the active Pd(0) species.
Figure 3. Influence of temperature: reactions were run for 12
h at 60 bar CO pressure using 50 mL NMP (1 M in acetamide
and 2 M in propionaldehyde), 0.25 mol % catalyst, 35 mol %
LiBr, 1.5 mol % H2SO4.
Figure 4. Influence of temperature and pressure: reactions
were run for 12 h at 60 bar CO pressure using 50 mL NMP (1
M in acetamide and 2 M in propionaldehyde) and 0.25 mol %
catalyst, 35 mol % LiBr, 1.5 mol % H2SO4.
The importance of bromide ions as co-catalysts has
been shown in previous studies (Schemes 3 and 4).
Standard palladium-catalyzed amidocarbonylation pro-
512
Adv. Synth. Catal. 2003, 345, 510 516

Synthesis of N-Acetyl-a-aminobutyric Acid via Amidocarbonylation
FULL PAPERS
cedures used typically 35 mol % LiBr as halide source. (up to 3 mol %) slightly decreased the target yield. The
Bromide salts constitute major byproducts of the PdBr2/PPh3 catalyzed reactions were very sensitive to
reaction and are desirable to be reduced. Unfortunately, the acid concentration. However, best yield were
it has been shown earlier that the yield of the amino acid obtained with 0.5 mol % H2SO4. A further increase of
is significantly decreased at lower halide concentra- acid content significantly reduced the product yield.
tions.[21] Apart from the halide co-catalyst, the presence This major influence of the concentration of the acid co-
of a Br˘nsted acid (e.g., H2SO4) has an enhancing effect catalyst might be assigned to the high reactivity of
on the palladium-catalyzed amidocarbonylation of propionaldehyde in aldol condensation reactions.
aldehydes. Standard procedures utilized 1 mol %
Next, we looked for synergistic effects of the two co-
H2SO4, though no detailed investigations on the optimal catalysts (BrÀ, H ) under the optimized conditions. As
composition have been performed so far. In order to shown in Figure 7, the concentration of H2SO4 has a less
carefully analyze the solitary effects of both co-catalysts, pronounced effect at high-pressure conditions. It appears
the employed concentrations of LiBr and H2SO4 were that the required LiBr and H2SO4 concentrations affect
varied independently (Figures 5 and 6). As potential the yield in an additive manner. This behavior might be
synergistic effects of both co-catalysts have been largely explained by a Lewis acid catalysis effect of Li cations.
‡
neglected in the past, they were also subject of our
Due to the significant differences between the phos-
investigations. We especially aimed at lowering the phine-ligated and phosphine-free catalyst systems, fur-
required bromide concentration by fine tuning the ther investigations focused on optimizations of the
‡
employed H concentration.
A study of the influence of the bromide concentration
on the yield of N-acetyl-a-aminobutyric acid (2) dem-
onstrated the superiority of the phosphine-ligated
catalyst system over the phosphine-free catalyst at low
bromide concentrations. For the first time, the palla-
dium-catalyzed amidocarbonylation gave high product
yields at low halide concentrations when CO pressures
of ꢀ 100 bar were applied. With as little as 5 10 mol %
LiBr, the yield of N-acetyl-a-aminobutyric acid was still
in the > 80% region (Figure 5).
As shown in Figure 6, minor changes in the acid
concentration resulted in major changes of the product
yield. Hence, it seemed very important not only to add a
™drop of sulfuric acid∫ (common lab practice), but to
measure the actual amount of added acid co-catalyst
accurately. The PdBr2 and (PPh3)2PdBr2 systems be-
haved quite differently. With PdBr2, the product yield
Figure 6. Influence of co-catalyst H2SO4: reactions were run
for 12 h at 60 bar CO pressure and 100 8C using 50 mL NMP
(1 M in acetamide and 2 M in propionaldehyde) and 0.25
increased by roughly 52% (up to 88%) upon addition of mol % catalyst, 35 mol % LiBr.
1.5 mol % H2SO4. A further increase of the acid content
Figure 7. Determining synergistic effects of co-catalysts LiBr
Figure 5. Influence of co-catalyst LiBr: reactions were run in
the six-fold parallel autoclave for 12 h at 100 8C using 15 mL
NMP (1 M in acetamide and 2 M in propionaldehyde) and
0.25 mol % catalyst, 1.5 mol % H2SO4.
and H2SO4: reactions were run in the six-fold parallel
autoclave for 12 h at 60 bar CO pressure using 15 mL
NMP (1 M in acetamide and 2 M in propionaldehyde) and
0.25 mol % PdBr2/2 PPh3.
Adv. Synth. Catal. 2003, 345, 510 516
513

Dirk Gˆrdes et al.
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O
O
O
X
NH
O
[Pd], CO
N
H
CO2H
N
H
N
H
O
12
2
H2N
[X-]
O
O
O
O
[H+]
H2N
H
N
N
H
+ H2O
14
O
O
+ H2O
+ H2O
H
H
[H+]
[H+]
O
O
O
O
H2N
[H+]
N
H
N
H
+ H2O
15
13
Figure 8. Influence of ligand to metal ratio: reactions were
run in the six-fold parallel autoclave for 12 h at 100 8C using
15 mL NMP (1 M in acetamide and 2 M in propionaldehyde)
and 0.25 mol % PdBr2, PPh3, 10 mol % LiBr, 1.5 mol %
H2SO4.
Scheme 5. Major equilibrating species in propionaldehyde-
acetamide condensation reactions and palladium-catalyzed
amidocarbonylation reaction.
Obviously, the decrease of the catalyst amount
phosphine/palladium ratio. Interestingly, minor varia- significantly favors non-metal catalyzed reactions to-
tions of the PPh3 concentration had a major effect on the ward various by-products. In addition to the simple
product yield, especially at lower CO pressures (Fig- condensation products of propionaldehyde and acet-
ure 8). The highest product yield was obtained with an amide [1,1-bis(N-acetylamino)propane (12), 2-methyl-
equimolar Pd/P ratio.
2-pentenal (13), 1-propenylacetamide (14)], we also
Another issue that deserved further investigation was detected and isolated two double bond isomers of the
the reduction of the catalyst loading. While standard higher order condensation adduct N-(2-methyl-1,3-
procedures employed 0.25 mol % palladium catalyst pentadienyl)acetamide (15). This formal OppolzerÀ
precursor, further screening reactions addressed the Overman type aminodiene is generated by quasi
economic criteria associated with the high costs of telomerization of two molecules propionaldehyde with
palladium catalysts, and were thus performed with lower one molecule acetamide. Successful implementation of
catalyst loading (Table 1).
these aminodiene building blocks in new multicompo-
From recent investigations into related alkoxycarbo- nent coupling reactions for the synthesis of various
nylations we learned that it is sometimes necessary to carbo- and heterocyclic compounds has recently been
increase the P/Pd ratio at low palladium concentrations reported.[23]
to maintain optimal productivity.[22] Therefore, reac-
tions with different P/Pd ratios were performed using
0.05 and 0.01 mol % Pd. While the catalyst turnover Conclusion
number (TON) could be increased up to 2700, the
product yield dropped below a reasonable level. Con- The amidocarbonylation of propionaldehyde with acet-
sistently, analytical and preparative investigations of the amide to give N-acetyl-a-aminobutyric acid has been
reaction mixture revealed the presence of a variety of studied in detail. With regard to raw material costs and
condensation products (Scheme 5).
atom economy, this reaction constitutes the most
Table 1. Activity of Pd-catalysts in amidocarbonylation.[a]
ratio PPh3/
PdBr2
yield [%]
TON
0.05 mol % PdBr2
0.01 mol % PdBr2
0.05 mol % PdBr2
0.01 mol % PdBr2
2/1
5/1
10/1
25/1
48
38
9
15
27
25
5
960
760
180
20
1500
2700
2500
500
1
[a]
Reactions were run in the six-fold parallel autoclave for 12 h at 60 bar CO pressure and 100 8C using 15 mL NMP (1 M in
acetamide and 2 M in propionaldehyde), 10 mol % LiBr and 1.5 mol % H2SO4.
514
Adv. Synth. Catal. 2003, 345, 510 516

Synthesis of N-Acetyl-a-aminobutyric Acid via Amidocarbonylation
FULL PAPERS
(100 ), 58 (100), 43 (47), 28 (22); anal. calcd. for C6H11NO3
(145.16): C 49.65, H 7.64, N 9.65; found: C 49.58, H 7.60, N 9.72.
efficient approach to this amino acid derivative. Com-
pared to standard amidocarbonylation conditions, the
amount of halide co-catalyst could be significantly
reduced, which is central to a desired low-waste
approach. For the first time, an unexpected but signifi-
cant increase of the yield of N-acylamino acids was
observed when applying high-pressure conditions
(ꢀ100 bar CO) in the palladium-catalyzed amidocar-
bonylation. This observation should also be of impor-
tance for amidocarbonylations of other reactive alde-
hydes.
Acknowledgements
The authors gratefully acknowledge generous financial support
from Degussa AG, the state Mecklenburg-Western Pomerania
and the Bundesministerium f¸r Bildung und Forschung
(BMBF).
References and Notes
Experimental Section
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General Remarks
High pressure reactions were carried out in a 300-mL reactor
(No. 4561 Parr Company) with a magnet-driven propeller
stirrer or a 2000-mL reactor (No. 4522 Parr Company)
equipped with a six-fold parallel insert. Product analysis of
reaction mixtures was performed by HPLC analysis on a
¾
Hewlett Packard HP 1090 equipped with an Alphabond C18
column (Supelco Inc., 10 mm particle, 300 Â 4.6 mm) using an
eluent containing 93% (v/v) of an aqueous 0.225 M tetrame-
thylammonium hydroxide solution, 4.85% (v/v) methanol,
2.0% (v/v) acetonitrile and 0.15% (v/v) acetic acid; benzoic
acid as internal standard. All solvents and reagents were
purchased from commercial sources and used without further
purification.
NMR spectra were recorded on a Bruker ARX 400 in
DMSO-d6; chemical shifts (d) are given in ppm relative to
TMS, coupling constants (J) in Hz. IR (KBr): Nicolet Magna
550, wavenumbers in cmÀ1. MS (EI): AMD 402 (70 eV).
[3] a) M. F. Czarniecki, L. S. Lehmann, (to Schering), EP
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Typical Procedure for the Amidocarbonylation of
Propionaldehyde with Acetamide
A 100-mL Schlenk flask was charged with PdBr2 (0.125 mmol,
33.2 mg, 0.25 mol %), PPh3 (0.25 mmol, 33 mg, 0.5 mol %), LiBr
(17.5 mmol, 1.52 g, 35 mol %), and acetamide (0.05 mol, 2.96 g)
under an inert gas atmosphere. Then, NMP (40 mL), propion-
aldehyde (0.1 mol, 7.4 mL), and a solution of H2SO4 (0.375
mmol, 37.5 mg, 1.5 mol %) in NMP (1 mL) were added. The
solution was stirred until complete dissolution, and then
cannula-transferred to a 300-mL autoclave. The reaction was
pressurized to 40 bar CO, heated to 100 8C, and pressurized
again to the actual reaction pressure of 60 bar CO. After 12 h,
the gas was released and the reaction mixture was transferred
to a 250-mL flask. The volatile compounds were removed
under oil-pump vacuum (bp. of NMP ꢁ 207 8C!!), and the
residue was taken up in methanol (10 mL) and the HPLC
eluent (90 mL).
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Org. Chem. 2002, 22, 536; d) J. F. Knifton, Amidocarbo-
nylation, in Applied Homogeneous Catalysis with Metal
Complexes, (Eds.: W. A. Herrmann, B. Cornils), VCH,
Weinheim, 1996, pp. 159.
1
d,l-N-Acetyl-a-aminobutyric acid (2): H NMR: d ˆ 12.47
(bs, 1H, COOH), 8.06 (d, J ˆ 7.5 Hz, 1H), 4.07 (dt, J ˆ 5.2/7.9
Hz, 1H), 1.83 (s, 3H), 1.68 (m, 1H), 1.57 (m, 1H), 0.86 (t, J ˆ 7.3
Hz, 3H); 13C NMR: d ˆ 173.7, 169.4, 53.2, 24.4, 22.3, 10.4; IR
(KBr): n ˆ 3346, 2965, 2877, 1727, 1652, 1525, 1435, 1372, 1260,
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1065, 1038 cmÀ1. MS: m/z (rel. intensity) ˆ 145 ([M ], 3 ), 74
‡
Adv. Synth. Catal. 2003, 345, 510 516
515

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516
Adv. Synth. Catal. 2003, 345, 510 516