Synthesis of N-Lauroyl Sarcosine by Amidocarbonylation: Comparing Homogeneous and Heterogeneous Palladium Catalysts

Article abstract of DOI:10.1021/acs.oprd.7b00326

An improved system for the synthesis of N-acyl amino acids via Pd-catalyzed amidocarbonylation is reported. Utilizing inexpensive Pd black gives the industrially important surfactant N-lauroyl sarcosine in excellent yields (95%) on a multi-gram scale. Advantages of the new system include reusability, decreased process temperature, and, importantly, drastically decreased co-catalyst loading.

Full text of DOI:10.1021/acs.oprd.7b00326

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Full Paper
Synthesis of N-Lauroyl Sarcosine by Amidocarbonylation:
Comparing Homogeneous and Heterogeneous Palladium Catalysts
Sören Hancker, Stefanie Kreft, Helfried Neumann, and matthias Beller
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00326 • Publication Date (Web): 14 Nov 2017
Downloaded from http://pubs.acs.org on November 14, 2017
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Synthesis of NꢀLauroyl Sarcosine by
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Amidocarbonylation: Comparing Homogeneous and
Heterogeneous Palladium Catalysts
Sören Hancker, Stefanie Kreft, Helfried Neumann and Matthias Beller*
LeibnizꢀInstitut für Katalyse e. V. an der Universität Rostock, AlbertꢀEinsteinꢀStraße 29a,
18059 Rostock, Germany.
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KEYWORDS
Amidocarbonylation, NꢀLauroyl Sarcosine, Palladium Catalysis, NꢀAcyl Amino Acids.
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ABSTRACT
An improved system for the synthesis of Nꢀacyl amino acids via Pdꢀcatalysed
amidocarbonylation is reported. Utilising inexpensive Pd black gives the industrially important
surfactant Nꢀlauroyl sarcosine in excellent yields (95 %) on multiꢀgꢀscale. Advantages of the
new system include reusability, decreased process temperature and importantly a drastically
decreased coꢀcatalyst loading.
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INTRODUCTION
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ꢀ5
NꢀAcyl amino acids are of fundamental importance for chemistry and biology. In addition,
they are of specific industrial interest as this class of compounds possesses a variety of different
application fields. For example, pharmaceuticals such as Captopril or Nꢀacetyl cysteine, food
additives like Aspartame as well as surfactants such as Nꢀlauroyl sarcosine (1) depict Nꢀacyl
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amino acid derivatives as structural motives. The broad application range of amino acids as
integral part of peptides as well as proteins and the importance of amino acid derivatives as
building blocks for organic syntheses continue to attract the interest for more effective synthetic
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methodologies for their production.
Within the numerous possible syntheses for amino acids and their derivatives, the
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amidocarbonylation, also known as Wakamatsu reaction, displays an interesting approach due
to the perfect atom efficiency. Complementary to the more common carbonylation reactions of
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olefins
or aryl halides,
this methodology employs readily accessible (in situ generated)
aldehydes combined either with amides, nitriles, acetals or epoxides.
While commercial routes for Nꢀacyl amino acids, combining the Strecker reaction with
subsequent acylation, produce overꢀstoichiometric amounts of salt waste, the
amidocarbonylation only results in the (coꢀ)catalysts as “byꢀproducts”. Originally developed
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using Co (CO) as catalyst,
nowadays the palladiumꢀcatalysed methodology utilising lithium
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bromide and sulfuric acid as coꢀcatalysts prevails in this area. Notably, this latter protocol
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further enhanced the substrate scope of the reaction.
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Figure 1. Comparison of the industrial synthesis of Nꢀlauroyl sarcosine and the
amidocarbonylation pathway.
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Due to the high foamꢀforming quality and good dermatological compatibility, long chain
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sarcosinates are of increasing interest as green detergents, which are produced in a quantity of
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0 000 tonnes per year. As an example the commercial synthesis of Nꢀlauroyl sarcosine is
realised by reacting sarcosine with Nꢀlauroyl chloride under SchottenꢀBaumann reaction
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conditions (Figure 1). Despite a decreased reactivity towards secondary amides, Lin and
Knifton successfully synthesised Nꢀlauroyl sarcosine in 95% overall yield employing 1 mol% of
Co (CO) and 200 bar CO/H at 120 °C via amidocarbonylation of Nꢀmethyl dodecanamide with
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paraformaldehyde (PFA). Further investigations by Hoechst AG gave the surfactant in a two
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staged pilot plant process.
While the amidocarbonylation theoretically incorporates every substrate atom in the product
molecule, the Pdꢀcatalysed procedure requires significant amounts of lithium bromide (35 mol%)
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and sulfuric acid (1 mol%) as coꢀcatalysts.
Likewise, these additives were essential in the
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first reported heterogeneously catalysed amidocarbonylation using Pd/C.
Herein, we describe an improved amidocarbonylation procedure using a novel heterogeneous
Pd catalyst, which allowed to drastically reduce the lithium bromide loading to 2.5 mol%.
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RESULTS AND DISCUSSION
Table 1. Comparison of various heterogeneous catalysts with PdBr for the model reaction.
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Entry
Catalyst
NMRꢀyield
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PdBr2
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Pd black
Pd/C (ox.)
Pd/SiO2
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Pd/Al O
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Pd/N@Gr
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Pd/Faujasite A 30
Pd/ZSMꢀ5 A 12
Pd/Faujasite B <5
Pd/ZSMꢀ5 B 50
General reaction conditions: 1 mmol Nꢀmethyl dodecanamide, 2 mmol PFA, 35 mol% LiBr,
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a
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mol% H SO , 1 mL NMP, Pd catalyst (1 mol% metal) at 100 °C and 60 bar CO for 16 h.
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b
Ethylene carbonate was added as internal standard. Integration results are based on
RꢀCH ꢀCOOH. 0.5 mol% PdBr .
c
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The amidocarbonylation of Nꢀmethyl dodecanamide with PFA towards Nꢀlauroyl sarcosine
was chosen as the model reaction since the industrially relevant product represented the main
interest of this study. An initial catalyst examination was conducted employing 35 mol% lithium
bromide and 1 mol% sulfuric acid at 100 °C and 60 bar of CO as reaction parameters (Table 1).
These conditions were selected based on prior findings from the first reported heterogeneously
catalysed amidocarbonylation applying Pd/C. For comparison, the reaction utilising 0.5 mol%
PdBr resulted in an overall yield of 77%. When the reaction was carried out with 1 mol% of
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simple palladium black, 52% of the desired surfactant was detected. Charcoal supported
palladium in the oxidic form led to a slightly decreased yield of 42%. In order to survey common
supports for heterogeneous catalysts, SiO ꢀ and Al O ꢀbased palladium catalysts were evaluated.
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While Pd/SiO gave the desired product in an insignificantly lower yield of 48%, using
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aluminium oxide as support entails only 22% of Nꢀlauroyl sarcosine. Surprisingly, a more basic
nitrogenꢀdoped graphene supported palladium catalysts resulted in the formation of 48% of the
glycine derivative. Apparently, this catalyst performs in a similar manner as palladium black
which is contrary to expectations since the nitrogen doping of the graphene results in basic
centres assumed to impede the acidꢀcatalysed amidocarbonylation. Additionally, ZSMꢀ5ꢀ and
Faujasiteꢀbased palladium catalysts were synthesised in order to test those acidic materials for
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positive effects. For each support, wet impregnation (A) and incipient wetness impregnation
(B) was used to prepare the heterogeneous metal nanoparticles. In general, all resulting catalysts
demonstrated a certain activity in the model amidocarbonylation reaction. However, only minor
conversion was observed in the presence of Pd/Faujasite B (<5%) and Pd/ZSMꢀ5 A (12%). A
moderate yield of 30% was provided by Pd/Faujasite A, while using Pd/ZSMꢀ5 B as catalyst the
product was obtained in 50% yield, similar to the initially tested palladium black. Apparently,
the catalyst support does not improve the reaction output. In addition, there is no obvious
tendency regarding the basic or acidic character of the support. Due to the commercial
availability and sufficient performance, we continued our investigations utilising Pd black as
catalyst.
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Table 2. Optimisation of the reaction conditions in the amidocarbonylation of Nꢀmethyl
dodecanamide with PFA towards Nꢀlauroyl sarcosine.
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5 mol% LiBr
X mol% H SO
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X mol% Pd black
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N
n-C H
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NH
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1 mL NMP, X °C
H
H
O
60 bar CO, 16 h
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Entry
H SO /mol%
Pd black/mol% PFA/mmol
T/°C
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NMRꢀyield
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General reaction conditions: 1 mmol Nꢀmethyl dodecanamide, X mmol PFA, 35 mol% LiBr,
b
X mol% H SO , X mol% Pd black, 1 mL NMP at X °C and 60 bar CO for 16 h. Ethylene
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carbonate was added as internal standard. Integration results are based on RꢀCH ꢀCOOH. Given
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in %.
To improve the product yield, temperature as well as acid and catalyst concentrations were
varied (Table 2). For example, an increased loading of sulfuric acid up to 10 mol% enhanced the
yield of 1 to 84%. Half of the amount of the acid gave 80% Nꢀlauroyl sarcosine. To our delight,
the overall yield was further enhanced when the reaction was carried out at lower temperatures.
Both at 80 °C and 60 °C, product 1 was formed with 87% efficiency. However, at 40 °C the
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reaction yielded only 8% of the desired surfactant. Investigations aiming to decrease the
necessary palladium loading proved that a catalyst content of 1 mol% is required to achieve
approximately full conversion. A reduction to 0.5 mol% of palladium black led to a diminished
output of 52% of 1. While the influence of the catalyst content appears to be strong, neither a
significant excess nor the application of exactly one equivalent of PFA drastically affected the
outcome of the amidocarbonylation as the deviation in the overall yield accounts for only 4% in
both cases.
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Chart 1. Influence of lithium bromide content.
X mol% LiBr
O
O
O
10 mol% H
1 mol% Pd black
mL NMP, 60 °C
0 bar CO, 16 h
2 4
SO
OH
+
n-C11H23
N
n-C11H
23
NH
H
H
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O
1
100
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5
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35
LiBr (mol%)
General reaction conditions: 1 mmol Nꢀmethyl dodecanamide, 1.5 mmol PFA, X mol% LiBr,
0 mol% H SO , 1 mol% Pd black, 1 mL NMP at 60 °C and 60 bar CO for 16 h. Ethylene
1
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carbonate was added as internal standard. Integration results are based on RꢀCH ꢀCOOH.
2
Next, the effect caused by the concentration of lithium bromide was briefly evaluated. As
shown in Chart 1, the amount necessary to obtain good product yields can be significantly
decreased from 35 mol% down to 2.5 mol%. Clearly, reducing the loading of the coꢀcatalyst by
more than 90% lowers the expenses for the process considerably. Likewise, the overall atom
efficiency is improved as well. The results indicate that a lithium bromide addition of more than
2.5 mol% does not positively affect the product formation since the experiments utilising 2.5, 5,
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0 and 35 mol% each lead to 90% ± 1% overall yield. However, reducing the coꢀcatalyst loading
to 1 mol% gave only 20% of the target substance. In agreement with previous work no surfactant
was produced in the absence of lithium bromide.
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Chart 2. Recycling experiments.
2
.5 mol% LiBr
O
O
O
10 mol% H SO
2
4
OH
+
1 mol% Pd black
n-C11H
23
N
n-C11H23
NH
H
H
1 mL NMP, 60 °C
O
60 bar CO, 16 h
1
100
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Run
General reaction conditions: 1 mmol Nꢀmethyl dodecanamide, 1.5 mmol PFA, 2.5 mol% LiBr,
10 mol% H SO , 1 mol% Pd black, 1 mL NMP at 60 °C and 60 bar CO for 16 h. After the initial
cycle, the particles were separated by centrifugation. The catalyst was washed with NMP and
again separated by centrifugation. This process was repeated five times before the particles were
transferred to the next set of the reaction. Ethylene carbonate was added as internal standard.
2
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Integration results are based on RꢀCH ꢀCOOH.
2
In order to evaluate the reusability of palladium black, this material was tested in recycling
experiments. Therefore, the reaction was conducted under optimised conditions with subsequent
isolation of the catalyst particles by centrifugation. In order to both reuse the particles and
determine the reaction yield by NMR, the isolated particles were washed with NMP several
times. The solvent was removed from the combined organic layers and the crude product was
analysed by NMR with internal standard while the particles were transferred into the vial
equipped with the next set of reaction compounds. As shown in Chart 2, a loss of activity of
circa 10% was detected after every run. The decreasing yield is explained either by deactivation
of the catalyst or loss of catalytically active material in the recycling process.
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Figure 2. Substrate scope of the Pd black catalysed amidocarbonylation.
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Conditions A: 1 mmol amide, 1.5 mmol aldehyde, 2.5 mol% LiBr, 10 mol% H SO , 1 mol%
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Pd black, 1 mL NMP at 60 °C and 60 bar CO for 16 h. Conditions B: 1 mmol amide, 1.5 mmol
aldehyde, 35 mol% LiBr, 1 mol% H SO , 1 mol% Pd black, 1 mL NMP at 120 °C and 60 bar
2
4
CO for 16 h. NMRꢀyields were determined using ethylene carbonate as internal standard.
Integration results are based on RꢀCH ꢀCOOH. Yields are given in %; isolated yields are given
2
in parentheses.
Having an improved protocol for the preparation of Nꢀlauroyl sarcosine in hand, we
investigated the reaction of three aldehydes and seven amides using the optimal protocol and
compared it to more severe conditions (Figure 2). Unfortunately, the reaction of PFA with
acetamide, 2ꢀpyrrolidinone and benzamide using conditions A did not provide access to the
corresponding glycine derivatives. On the other hand, the corresponding products were obtained
when the reaction was carried out at 120 °C with 35 mol% lithium bromide and 1 mol% sulfuric
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acid (conditions B). More specifically, Nꢀacetyl glycine (2) was formed in 57% NMRꢀyield
(45% isolated) and the conversion of 2ꢀpyrrolidinone gave 80% NMRꢀyield (68% isolated yield)
of the corresponding 2ꢀoxoꢀ1ꢀpyrrolidineacetic acid (3). Notably, the corresponding amide
Piracetam draws interest as pharmaceutical for potential treatment of dementia. Furthermore, Nꢀ
benzoyl glycine (5) was synthesised with 44% NMRꢀyield (30% isolated yield). However, when
caprolactam was reacted with PFA at 60 °C (Cond. A) the corresponding caprolactam acetic acid
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(4) was obtained in 73% NMRꢀyield (65% isolated yield). Under more severe conditions at
120°C, the product was synthesised in 80% NMRꢀyield. Despite the more forcing reaction
conditions B, butanediamide and 2ꢀcyano acetamide failed to convert to the corresponding
glycine derivatives (6 and 7).
Figure 3. Comparison of the influence of a present Nꢀalkylation on the activity of the substrate
in the amidocarbonylation with substituted aldehydes.
Conditions A: 1 mmol amide, 1.5 mmol aldehyde, 2.5 mol% LiBr, 10 mol% H SO , 1 mol%
2
4
Pd black, 1 mL NMP at 60 °C and 60 bar CO for 16 h. NMRꢀyields were determined using
ethylene carbonate as internal standard. Integration results are based on RꢀCH ꢀCOOH.
2
Next, we compared the amidocarbonylation of isovaleraldehyde with acetamide and Nꢀmethyl
acetamide in order to elucidate the influence of an additional Nꢀalkyl substituent (Figure 3).
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Under identical reaction conditions, Nꢀacetyl leucine can be synthesised in 20% NMRꢀyield,
while NꢀacetylꢀNꢀmethyl leucine is not formed at all.
Figure 4. Results from the amidocarbonylation of Nꢀmethyl dodecanamide with PFA towards Nꢀ
lauroyl sarcosine on a 10 gꢀscale.
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2.5 mol% LiBr
1
0 mol% H SO
O
2
4
O
O
1
mol% Pd black
1 mL NMP, 60 °C
0 bar CO, 16 h
OH
+
n-C H
11 23
N
n-C11H23
NH
H
H
O
6
1
1
0 g
95%
Conditions: 46.8 mmol Nꢀmethyl dodecanamide, 70.3 mmol PFA, 2.5 mol% LiBr, 10 mol%
H SO , 1 mol% Pd black, 46.8 mL NMP at 60 °C and 60 bar CO for 16 h.
2
4
As shown in Figure 4 our improved protocol can be easily performed on a 10 gꢀscale. To our
delight, employing a slightly modified workꢀup procedure, the compound is obtained in >98%
overall yield with the starting material as major impurity (<2%). An additional acidꢀbase
extraction further enhanced the purity of the product while the yield decreased to 95%. This
experiment suggests that the synthesis of 1 can be transferred to larger scales without significant
loss of catalyst activity.
Chart 3. ICPꢀOESꢀresults for Pdꢀcontent of different Nꢀlauroyl sarcosine samples.
500
4
3
00
00
200
1
00
0
A
B
C
D
Sample N-lauroyl sarcosine
Sample A: Prepared by separating the catalyst from the reaction mixture by centrifugation,
washing with NMP and subsequently removing the solvent to obtain the crude product. Sample
B: Substance obtained after the first purification step. Sample C: Substance obtained after
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complete purification procedure. Sample D: Substance obtained after complete purification
procedure of the PdBr ꢀcatalysed reaction.
2
To get insight into the degree of palladium leaching from the heterogeneous catalyst, analysis
of the metal contamination in product 1 was executed. Therefore, palladium contents of the
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(crude) products from 1 and 47 mmolꢀscale experiments were determined by ICPꢀanalysis. For
comparison, also a sample generated by carrying out the reaction with PdBr was investigated.
2
As depicted in Chart 3, in all samples a significant amount of palladium was observed ranging
from 80 to 460 ppm. The crude product of sample A contained most palladium which accounts
for a loss of around 17% of the originally employed palladium black. The reasons for this loss of
palladium remain currently unknown. Sample B which is obtained after the first purification step
contained lower amounts of palladium (250 ppm). The palladium content could be further
reduced to 150 ppm by subsequent acidꢀbase extraction. Surprisingly, the product prepared by
employing the homogeneous catalyst was the lowest in residual palladium (80 ppm).
CONCLUSIONS
An improved palladium catalyst for the synthesis of the industrially important surfactant Nꢀ
lauroyl sarcosine is described. Investigating the amidocarbonylation reaction of Nꢀmethyl
dodecanamide with paraformaldehyde (PFA) in the presence of inexpensive Pd black gives the
desired product 1 in excellent yields (95%). Advantages of the new protocol include reusability,
decreased process temperature, and a significantly decreased coꢀcatalyst loading.
EXPERIMENTAL SECTION
General Information. The solvent (NMP) was flushed with argon and dried with molecular
sieves overnight. Subsequently, the sieves were filtered off and the resulting NMP was distilled
ꢀ3
1
at 70 °C in high vacuum (10 mbar). Both steps were conducted under argon atmosphere. H and
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C NMR spectra were recorded on Bruker AV 300, Bruker Fourier 300 and Bruker AV 400
NMR spectrometers. Chemical shifts are reported in ppm relative to the deuterated solvent
1
13
(DMSOꢀD : H: 2.500 ppm; C: 39.520 ppm). High resolution mass spectra were recorded on an
6
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Agilent 1200/6210 TimeꢀofꢀFlight LCꢀMS by electrospray ionization. Elemental analyses were
conducted utilising a Leco TruSpec Micro CHNS Element Analysator. ICPꢀOES measurements
were conducted on a Varian/Agilent 715ꢀES instrument.
Catalyst Preparation. Pd/SiO , Pd/Faujasite A and Pd/ZSM-5 A (all 1 wt.% Pd). Pd/SiO was
2
2
prepared by wet impregnation. Silica (990 mg, 0.035ꢀ0.070 mm, pore diameter 6 nm) was added
to a solution of 30 mL water and Pd(NO ) ꢁXH O (25 mg, ca. 40% Pd content). After 30 minutes
3
2
2
of stirring, the liquid was removed by rotary evaporation. Subsequently, the material was further
dried at 80 °C overnight. Finally, the catalyst was calcined at 500 °C for 2 hours to give the final
product. Pd/Faujasite A and Pd/ZSM-5 A were synthesised accordingly.
Pd/Faujasite B and Pd/ZSM-5 B (both 1 wt.% Pd). Pd/Faujasite B and Pd/ZSMꢀ5 B were
prepared by incipient wet impregnation. Therefore, Pd(NO ) ꢁXH O (25 mg, ca. 40% Pd content)
3
2
2
was dissolved in water (1.2 mL for Faujasite and 0.8 mL for ZSMꢀ5). The solution was added to
990 mg of supporting material. The catalysts were dried at 80 °C overnight and finally calcined
at 500 °C for 2 hours to give the final product.
Pd/N@Gr (3 wt.% Pd) was synthesised by pyrolysis of a mixture of [Pd(phenanthroline)Cl2]
and carbon powder. For the synthesis of [Pd(phenanthroline)Cl ], [Pd(CH CN) Cl ] (2.233
2
3
2
2
mmol, 579 mg) was added dropwise to a stirred solution of phenanthrolineꢁH O (4.925 mmol,
2
976 mg) and 60 mL DMF at 150 °C. After the formation of a precipitate within a few minutes,
the mixture is heated under reflux conditions for another 3 hours. The product was obtained as
orange needles after filtration. Subsequently, [Pd(phenanthroline)Cl ] (0.314 mmol, 112.23 mg)
2
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was dissolved in 60 mL DMF at 120 °C. Henceforward, carbon powder (888.42 mg, VULCAN
XC72R) was added and the mixture was kept at 120 °C for 2 hours. The solvent was removed by
vacuum and the solid was further dried for 15 h at 120 °C in high vacuum. Finally, the catalyst
was obtained by pyrolysis of the material at 800 °C for 2 h under argon atmosphere.
0
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General amidocarbonylation procedure. The manipulations were carried out in a 300 mL
Parr high pressure autoclave. The small scale experiments were conducted in 4 mL glass vials
using magnetic stirring bars. Prior to the reaction (example table 2, entry 11 in parentheses), the
vials were placed on an appropriate plate and equipped with the solid compounds (213.4 mg
Nꢀmethyl dodecanamide (1 mmol), 45 mg PFA (1.5 mmol), 30.4 mg lithium bromide (35
mol%), 1.1 mg Pd black (1 mol%)) which were subsequently sealed with a septum cap and
evaporated and flushed with argon for three times. Afterwards, NMP (1 mL; waterꢀfree stored
under Argon) was added prior to 5 µL sulfuric acid (10 mol%; concentrated, neither purified nor
oxygenꢀ or waterꢀfree). The autoclave was closed before it was evaporated and flushed with
Argon for three times as well. The autoclave was opened and the plate with the vials was placed
inside quickly before the autoclave was closed again. Afterwards, the autoclave was flushed with
argon for 15 minutes. The autoclave was sealed tightly before it was flushed with carbon
monoxide up to 3 bars for three times. The reaction pressure (60 bars CO) was added by aid of
the digital pressure indication. The autoclave was regulated by a control unit which monitored
the reaction temperature via an integrated thermometer. The temperature was adjusted to the
given value by the control unit automatically. The experiment was conducted at the
corresponding reaction temperature for 16 hours. Subsequently to the reaction, the autoclave was
cooled in an ice bath. At room temperature, the pressure was released slowly. The heterogeneous
catalyst was separated either by centrifugation (recycling experiments, preparation of sample A)
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or by filtration (optimisation reactions, substrate scope, 10 gꢀscale experiment, preparation of
samples BꢀD) and washed at least three times within the process. Whenever NMP was removed
(70 °C in high vacuum), an antiꢀsplash guard with returnꢀhole (Sigma Aldrich) was utilized since
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the solvent condensed before reaching the condensation trap. After the removal of NMP, the
crude product was obtained.
Optimisation reactions. The reaction solution was filtered through filter paper. The paper was
washed with NMP several times. Ethylene carbonate (0.25 mol% to the amide) was added to the
crude product (viscous liquid). Acetone was added to guarantee equal dispersion of the NMR
standard within the sample. The acetone was removed by high vacuum. The integration results
are based on the four protons from ethylene carbonate and the two protons from the glycine
4
moiety (NꢀCH ꢀCOOH). Noteworthy, Nꢀacyl sarcosines exist as cisꢀ and transꢀisomers.
2
Therefore, the NꢀCH ꢀCOOH signal is split into one singlet at 3.96 ppm and one at 4.09 ppm.
2
The intensity distribution for Nꢀlauroyl sarcosine is 66:34. The signal splitting can also be
observed for the methyl group NꢀCH (2.79 ppm and 2.98 ppm, 34:66, singlet) and the first
3
CH ꢀgroup of the alkyl chain CH ꢀCH ꢀCOꢀN (2.16 ppm and 2.30 ppm, 34:66, triplet, J = 7.4
2
2
2
Hz).
Recycling experiments. After the reaction, the mixture was transferred under argon into a
septum sealed centrifuge tube. After centrifugation (5000 U/min for 20 min), the supernatant
solution was removed via syringe and collected. The particles in the tube were washed with
NMP five times. The combined NMP layers were prepared for NMR analysis (analogue to
“Optimisation reactions”). The particles were transferred via syringe with NMP under argon into
the next vial already containing the next set of reaction substrates as well as lithium bromide. In
order to transfer the catalyst as entirely as possible, NMP was added in 0.1 mL portions and then
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transferred into the vial. This was repeated 10 times in order to add 1 mL NMP over the entire
process as solvent for the next run. Finally, sulfuric acid was added and the manipulations were
pursued as usual (see “General amidocarbonylation procedure”). After the reaction, the particles
were treated with this procedure again until the forth cycle.
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Substrate scope. The reactions were conducted and analysed by NMR and therefore treated
according to the manipulations described in the sections “General amidocarbonylation
procedure” and “Optimisation reactions”. In order to determine the isolated yield, the reaction
was repeated and an acidꢀbase extraction was conducted in contrast to the optimisation reactions.
Therefore, the crude product was dissolved in saturated aqueous NaHCO solution (reaction is
3
complete when evolution of gas stops and the liquid/particles are dissolved). The aqueous
solution was extracted with ethyl acetate three times. Subsequently, the aqueous phase was
acidified with concentrated phosphorus acid to pH 3. The aqueous phase was extracted with
ethyl acetate again three times. The combined organic layers were dried over Na SO which was
2
4
later filtered off. Ethyl acetate was removed on the rotary evaporator. The products were dried in
high vacuum.
10 g-scale experiment. The solid substrates and catalysts were added directly into the
autoclave which was equipped with a mechanic stirrer. The autoclave was closed, evaporated
and flushed with argon for three times. Meanwhile, a Schlenk flask was evaporated and flushed
with argon as well. NMP and sulfuric acid were added and mixed by stirring with a magnetic
stirring bar. The resulting solvent was added into a syringe and the autoclave was opened
carefully. Under argon counter flow, the top of the autoclave was lifted slightly and the solvents
were injected into the autoclave. Subsequently, the autoclave was closed and flushed with argon
for 15 minutes. The carbon monoxide pressure was added after flushing with CO and heating as
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well as stirring was started. After the reaction, the pressure was released very slowly. The
reaction mixture was filtered through filter paper before the solvent was removed in high vacuum
at 70 °C (see “General amidocarbonylation procedure”). Water was added to the crude product at
atmospheric pressure and 70 °C. After stirring for a few minutes, the two phase system was
stored in a deep freezer at ꢀ28 °C for one hour. Afterwards, the solid was allowed to warm up to
room temperature until the water melted. The solid raw product was crushed into small particles
with a scoopula on a frit (POR 3) and subsequently washed with water five times. The product
resulting from this purification step was analysed by ICPꢀOES and NMR as sample B. For
additional purification, the acidꢀbase extraction described within the section “Substrate scope”
was conducted. For Nꢀlauroyl sarcosine, the product starts to separate from the aqueous phase as
an additional liquid phase between pH of 4ꢀ6. The separation occurs immediately during the
addition of concentrated phosphorus acid. After the two phase system was formed, a few more
drops of concentrated phosphorus acid were added in order to ensure that the product can be
obtained entirely. Additionally, the aqueous phase was extracted with ethyl acetate three times.
The combined organic layers were dried over Na SO . After the solid was filtered off, ethyl
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acetate was removed using a rotary evaporator. The resulting viscous liquid was dried in high
vacuum. The resulting Nꢀlauroyl sarcosine was further analysed as sample C by ICPꢀOES and
NMR.
ICP-OES analysis. Samples B and C were prepared as described in the section “10 gꢀscale
experiment”. Sample A was prepared by conducting the experiment on the optimisation scale
(conditions table 2, entry 11; see section “General amidocarbonylation procedure”). After the
reaction, the particles were removed by centrifugation (5000 U/min for 20 min) and the
remaining solid was washed with NMP five times. The crude product was analysed by ICPꢀOES
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and NMR as Sample A. Sample D was prepared by conducting the reaction utilising PdBr (0.5
2
mol%, 6.2 mg) as catalyst under otherwise optimised reaction conditions on a 1 gꢀscale (4.69
mmol Nꢀmethyl dodecanamide) in a 8 mL vial (see section “General amidocarbonylation
procedure”). The product was isolated according to the conditions described in section “10 gꢀ
scale experiment”. Therefore, the sample was generated in the identical manner as sample C. The
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substance obtained from the PdBr ꢀcatalysed reaction was analysed as sample D by ICPꢀOES
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and NMR.
1
13
Analytical data
.
All δ H and δ C in ppm, all coupling constants J in Hz.
1
N-Lauroyl sarcosine (1): Offꢀwhite solid (12.04 g, 95%). H NMR (300.1 MHz, DMSOꢀd ):
6
1
δ H = 0.83ꢀ0.88 (3H, m, CH ), 1.19ꢀ1.30 (16H, m, 8 CH ), 1.40ꢀ1.52 (2H, m, CH ), 2.16 (0.68H,
3
2
2
A
A
C
C
t, J = 7.4, H ), 2.30 (1.32H, t, J = 7.4, H ), 2.79 (1.02H, s, H ), 2.98 (1.99H, s, H ), 3.96 (1.32H,
B
B
13
13
s, H ), 4.09 (0.68H, s, H ), 12.61 (1H, br s, COOH); C NMR (75.5 MHz, DMSOꢀd ): δ C =
6
13.9 (CH ), 22.1 (CH ), 24.5 & 24.6 (CH ), 28.7 (2 C, CH ), 28.9ꢀ29.0 (4 C, CH ), 31.3 (CH ),
3 2 2 2 2 2
A
C
B
3
1.8 & 32.1 (C H ), 34.2 & 36.0 (C H ), 48.9 & 50.9 (C H ), 170.8 & 171.0 (COꢀN), 172.6 &
2
3
2
ꢀ
+
172.6 (COOH); HRMS (ESI, m/z): calcd. for C H NO (MꢀH ): 270.20747, found:
1
5
28
3
270.20746; EA: calcd. for C H NO : C 66.38%, H 10.77%, N 5.16, found C 66.55%, H
15 29 3
10.55%, N 5.00%.
1
1
N-Acetylglycine (2): Offꢀwhite solid (52.7 mg, 45%). H NMR (300.1 MHz, DMSOꢀd ): δ H =
6
13
1
.84 (3H, s, CH ), 3.71 (2H, d, J = 5.7, CH ), 8.15 (1H, t, J = 5.7, NH); C NMR (75.5 MHz,
3
2
1
3
q
q
DMSOꢀd ): δ C = 22.3 (CH ), 40.7 (CH ), 169.7 (C ), 171.5 (C ); HRMS (ESI, m/z): calcd. for
6
3
2
ꢀ
+
C H NO (MꢀH ): 116.03532, found: 116.03529; EA: calcd. for C H NO : C 41.03%, H 6.03%,
4
6
3
4
7
3
N 11.96%, found C 41.19%, H 6.01%, N 11.63%.
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2
-Oxo-1-pyrrolidineacetic acid (3): This product was further purified by sublimation in high
ꢀ3
1
vacuum (10 mbar) at 100 °C. Offꢀwhite solid (97.3 mg, 68%). H NMR (300.1 MHz, DMSOꢀ
1
d ): δ H = 1.94 (2H, p, J = 7.4, CH ), 2.23 (2H, t, J = 8.1, CH ), 3.38 (2H, t, J = 7.0, CH ), 3.90
6
2
2
2
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13
13
(
2H, s, CH ), 12.71 (1H, br s, COOH); C NMR (75.5 MHz, DMSOꢀd ): δ C = 17.5 (CH ),
2
6
2
q
q
29.9 (CH ), 43.6 (CH ), 47.0 (CH ), 170.2 (C ), 174.4 (C ); HRMS (ESI, m/z): calcd. for
2
2
2
ꢀ
+
C H NO (MꢀH ): 142.05097, found: 142.05063; EA: calcd. for C H NO : C 50.35%, H 6.34%,
6
8
3
6
9
3
N 9.79%, found C 50.61%, H 6.50%, N 9.77%.
1
Hexahydro-2-oxo-1H-azepine-1-acetic acid (4): Offꢀwhite solid (111.3 mg, 65%). H NMR
1
(
300.1 MHz, DMSOꢀd ): δ H = 1.51ꢀ1.58 (2H, m, CH ), 1.60ꢀ1.70 (4H, m, 2 CH ), 2.41ꢀ2.45
6
2
2
1
3
(
2H, m, CH ), 3.37ꢀ3.40 (2H, m, CH ), 3.98 (2H, s, CH ); C NMR (75.5 MHz, DMSOꢀd ):
2
2
2
6
1
3
q
δ C = 22.9 (CH ), 27.7 (CH ), 29.3 (CH ), 36.3 (CH ), 49.9 (CH ), 50.2 (CH ), 171.1 (C ),
2
2
2
2
2
2
q
ꢀ
+
1
75.0 (C ); HRMS (ESI, m/z): calcd. for C H NO (MꢀH ): 170.08227, found: 170.08218; EA:
8 12 3
calcd. for C H NO : C 56.13%, H 7.65%, N 8.18%, found C 55.99%, H 7.52%, N 7.84%.
8
13
3
1
1
N-Benzoylglycine (5): Offꢀwhite solid (53.8 mg, 30%). H NMR (300.1 MHz, DMSOꢀd ): δ H
6
=
3.94 (2H, d, J = 5.9, CH ), 7.44ꢀ7.57 (3H, m, CH), 7.86ꢀ7.89 (2H, m, CH), 8.83 (1H, t, J = 5.9,
2
1
3
13
NH); C NMR (75.5 MHz, DMSOꢀd ): δ C = 41.3 (CH ), 127.3 (2C, CH), 128.5 (2C, CH),
6
2
q
q
q
ꢀ
+
1
31.5 (CH), 133.9 (C ), 166.7 (C ), 171.4 (C ); HRMS (ESI, m/z): calcd. for C H NO (MꢀH ):
9 8 3
1
78.05097, found: 178.05084; EA: calcd. for C H NO : C 60.33%, H 5.06%, N 7.82% , found C
9 9 3
60.61%, H 5.04%, N 7.72%.
ASSOCIATED CONTENT
Supporting Information Available:
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13
Hꢀ and CꢀNMR spectra and a list of the commercial sources for all chemicals. (PDF)
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AUTHOR INFORMATION
Corresponding Author
*
Email: matthias.beller@catalysis.de
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
We thank Maximilian Hertrich, Patrick Piehl, Sandra Leiminger, Karin Struve and the
analytical department for fruitful discussions and technical support. This work was supported by
the state of MecklenburgꢀVorpommern and the BMBF.
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