Iron porphyrins catalyze the synthesis of non-protected amino acid esters from ammonia and diazoacetates

Article abstract of DOI:10.1039/b609265a

Iron complexes of porphyrins (and corroles to a lesser extent) are the first catalysts to utilize ammonia for the synthesis of N-free amino acid esters. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b609265a

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Iron porphyrins catalyze the synthesis of non-protected amino acid
esters from ammonia and diazoacetates{
Iris Aviv and Zeev Gross*
Received (in Cambridge, UK) 30th June 2006, Accepted 1st September 2006
First published as an Advance Article on the web 20th September 2006
DOI: 10.1039/b609265a
glycine or alanine.5 The chemical reactions (condensation and
Iron complexes of porphyrins (and corroles to a lesser extent)
reductive amination) employed for that purpose are quite trivial
for ammonia and the same holds for the common laboratory and
industrial procedures (alkylation by haloacetic esters).6 The process
described here is fundamentally different: ammonia (as solvated
gas or ammonium salt) is reacted with the diazoacetates 1a or 1b
(Scheme 1) in what is at least formally a NH activation process.
This adds to the very rare cases where NH activation of ammonia
was observed in a condensed phase and/or utilized for synthetic
purposes.7
are the first catalysts to utilize ammonia for the synthesis of
N-free amino acid esters.
The synthesis of N-substituted glycine ethyl esters from amines and
ethyl diazoacetate (EDA) may be catalyzed by quite a variety of
metal complexes.1 Nevertheless, the iron complexes of triarylcor-
roles2 and tetraarylporphyrins were found to display unique
features. Full and very fast conversion was obtained by
simultaneous addition of equimolar amounts of the substrates to
the catalysts and the selectivity toward activation of the NH bonds
was absolute.3 These results contrast with those obtained with
most other catalysts, which often suffer from metal-poisoning by
excess amine, and which produce significant amounts of
byproducts from EDA coupling. Even the recently developed
copper-based catalysts operate at 4–10 mol%, require long reaction
times and gradual addition of the diazo compound (1–6 h),4 while
reactions with the iron-based catalysts (0.1 mol%) are complete
within seconds (Fig. 1b).3
The initial research was concerned with discovering whether
Rh2(OAc)4 or the iron complexes shown in Scheme 1 could
catalyze the reaction of ammonia with EDA. Despite the extensive
utilization of Rh2(OAc)4 as catalyst for the seemingly related
reactions of amines (or amides) with EDA,1f,8 solutions of
ammonia and EDA were not affected by this complex (entry 1,
Table 1). The iron corrole 6 was not inert under the same reaction
conditions (entry 2), which led to diethylmaleate (5a) from EDA
coupling as the main product and 3% of the trisubstituted amine
(triethyl nitrilotriacetate 4a).10a Much better selectivity to desired
products was displayed by the iron porphyrins 7a and 7b: only 4a
and the glycine ester 2a9 (i.e., no 5a or 3a) were formed and each of
these compounds could be obtained as sole product by controlling
the NH3 : EDA ratio. The triple activation product (4a)10 was
exclusively obtained when ammonium acetate was used as the
nitrogen source (entry 6). This result is indicative of insufficient
amounts of free ammonia under these conditions and the same
conclusion probably holds for the reactions performed in diethyl
Based on the superior results with amines, we now report
success in a much more challenging reaction: the use of ammonia
as the nitrogen atom source in the synthesis of the two smallest
amino acids. To the best of our knowledge, there is no reported
catalyst for the synthesis of N-free amino acid derivatives from
diazoacetates. This approach is also significantly different from the
biological processes, where ammonia is only utilized for transform-
ing a larger amino acid (or the corresponding a-keto ester) into
Fig. 1 Snapshots (full films available in ESI{) from the reactions of
EDA with (a) ammonia (9 s after addition) and b) aniline (3 s after
addition) in the presence of 1 mg 7b (3 mL THF, 153 mL EDA, 133 mL
aniline or 1 g NH4OAc), demonstrating the very fast emission of N2(g)
.
Department of Chemistry, Technion – Israel Institute of Technology,
Haifa, 32000, Israel. E-mail: chr10zg@tx.technion.ac.il;
Fax: +972 4829 5703; Tel: +972 4829 3954
{ Electronic supplementary information (ESI) available: NMR spectra
and GC retention times of the products and the full films (in quicktime
format) regarding the experiments described in Fig. 1. See DOI: 10.1039/
b609265a
Scheme 1
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Table 1 Products obtained from the reactions of ammonia with EDA
(1a, Scheme 1)a
Table 2 Products obtained from the reactions of ammonia with the
diazoester 1b (Scheme 1)a
Reaction
T/u C time/h
Reaction
T/u C time/min Selectivity
Entry Catalyst
Solvent ‘‘NH3’’
Gas
Selectivity
Entry Catalyst Solvent ‘‘NH3’’
1
2
Rh2(OAc)4 THF
6
25
25
24
5
No reaction
5a (97%)
4a (3%)
2a (73%)
4a (27%)
4a (100%)
2a (100%)
4a (100%)
1
2
7b
7b
7b
THF
THF
THF
Gas
NH4OAc 65
2b 65
65
3
2
2
2b (91%)
3b (9%)
2b (68%)
3b (32%)
3b (100%)
THF
Gas
3
7a
Ether
Gas
25
5
3
a
4
5
6
a
7b
7b
7b
Ether
THF
THF
Gas
Gas
25
25
3
Reaction conditions as in Table 1, except of the temperature.
1
10 min
Specific amounts of reagents and mol% relative to catalyst were as
follows. Entry 1: 20 mg 1b, 107 mol%, active NH3 purging. Entry 2:
20 mg 1b, 107 mol%, NH4OAc (1 gr, 12.9 mmol). Entry 3: 20 mg
1b, 107 mol%, 2b (18.3 mg, 0.156 mmol).
NH4OAc 25
The solutions (7 mL) containing all reagents and 1 mg catalyst
were mixed until complete disappearance of EDA was assured by
TLC. NMR spectroscopy, GC/MS, and GC were used for
identification of the reaction products and their relative yields.
Control reactions revealed that none of the products is obtained
without catalyst. Specific amounts of reagents and mol% relative to
catalyst were as follows. Entry 1: 118 mL EDA, 500 mol%. Entry 2:
50 mL EDA, 475 mol%. Entry 3: 100 mL EDA, 1000 mol%. Entry 4:
100 mL EDA, 651 mol%. Entry 5: 153 mL EDA 1000 mol% (0.2 M)
and either saturated NH3 solution (0.46 M) or under active NH3
purging. Entry 6: 153 mL EDA, 1000 mol%, NH4OAc (1 g,
12.9 mmol).
and diazoesters. Mechanistic investigations of this catalytic process
and advantageous extension of the unique features for synthetic
purposes are currently carried out in our laboratories and will soon
be reported.
The German–Israel Project Cooperation (DIP F 6.2) is grate-
fully acknowledged for financial support of this work.{
Notes and references
ether (entries 3–4). Consistent with this assumption, only the
product from single activation of ammonia (2a) was obtained
when the reaction was performed in either saturated NH3/THF
solution (0.46 M by titration vs. 0.20 M EDA) or under NH3 flow
(entry 5). The glycine ester 2a from these reactions was isolated as
the trifuoroacetic acid salt in 81 and 87% yield,11 respectively,
corresponding to 810–870 catalytic turnovers.
{ Procedure for quantitative reactions of ammonia with EDA, leading to
2a as exclusive product: THF (7 mL) was purged with ammonia gas for
15 minutes, leading a solution that is 0.46 M NH3 (titration). Neat EDA
(153 mL, 1.46 mmol, 0.2 M) was added to the solution, followed by solid
catalyst (1 mg, 1.46 mmol, 0.1 mol% relative to EDA). This induced a color
change from brown to red and nitrogen gas emission. The consumption of
EDA was followed by TLC examinations. The solvent (and residual
ammonia) was evaporated after 1 h, the oily residue was dissolved in
diethyl ether (1 mL), and TFA (0.11 mL) was added. The TFA salt of
glycine ethyl ester (mp = 138 uC)9 separated from the solution, yielding
257 mg (81% yield relative to EDA) as white salt. Alternatively, the
reaction was carried out under a slow stream of gaseous ammonia, yielding
275 mg (87% yield) after the same workup procedure.
The results presented so far clearly demonstrate that these
catalysts can utilize ammonia as the nitrogen atom source of
amino acid derivatives, that the reactivity of ammonia in this
system is only slightly smaller than of the produced amines (2a and
3a) and that the iron complex of the cheapest and most accessible
porphyrin (7b) is an excellent catalyst for the transformation. A
demonstration of these conclusions is provided in Fig. 1, which
compares the 7b-catalyzed reactions of EDA with ammonia (from
ammonium acetate) and aniline. Bubbles due to the release of N2
developed within seconds even in the reaction with ammonia,
although with aniline this occurred more vigorously. No reaction
took place under identical conditions within 24 h when Rh2(OAc)4
was used. Nitrogen evolution due to EDA decomposition started
only after all ammonia was evaporated and 5a and diethyl
fumarate were the sole products in that case.
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for the preparation of alanine esters as well (Scheme 1, R = CH3).
The methyl-substituted diazoester (ethyl diazopropionate, 1b)12
was less reactive than EDA and did not react with ammonia at
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corroles as well) are the first reported metal complexes to catalyze
the formation of N-free glycine and alanine esters from ammonia
4478 | Chem. Commun., 2006, 4477–4479
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