Stevens rearrangement as a tool for the structural modification of polyaminopolycarboxylic ligands

Article abstract of DOI:10.1039/c0ob00909a

Polyaminopolycarboxylic acids are a well known class of ligands employed for metal ion complexation. Despite the large commercial availability, reports of their use as substrates for direct structural modifications are rare. Herein we report a simple and

Full text of DOI:10.1039/c0ob00909a

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Stevens rearrangement as a tool for the structural modification of
polyaminopolycarboxylic ligands†
Giovanni B. Giovenzana,*a Daniela Imperio,a Luciano Lattuadab and Fulvio Uggerib
Received 20th October 2010, Accepted 15th November 2010
DOI: 10.1039/c0ob00909a
Polyaminopolycarboxylic acids are a well known class of
ligands employed for metal ion complexation. Despite the
large commercial availability, reports of their use as substrates
for direct structural modifications are rare. Herein we report
a simple and efficient protocol for the preparation of substi-
tuted polyaminopolycarboxylic ligands relying on a one-pot
N-alkylation–Stevens rearrangement cascade.
particularly impelling as recent molecular imaging applications
require tailor-made chelates whose structure has to be finely tuned
in order to attain a high and selective responsivity to a specific
biological or physicochemical parameter.14
Polyaminopolycarboxylic ligands nearly always embody car-
boxylic groups and tertiary amines. Both of these groups cannot
be used for structural modification or functionalization without
reducing the overall denticity of the ligand itself and this restricts
the potential modification sites to the molecule backbone carbon
atoms or to the methylene groups between the carboxylic acid
and the tertiary amine (a-carbon atoms). We choose the latter
sites because: (i) a-carbon atoms are “activated” towards different
chemical transformations by the concomitant proximity of two
functional groups and (ii) a-carbon atoms are represented in the
majority of polyaminocarboxylic ligands allowing their function-
alization to be applied to a wider array of substrates.
Polyaminopolycarboxylic ligands are the best known chelating
agents for metal ions.1 The importance of EDTA (1,2-
ethylenediamine-N,N,N¢,N¢-tetraacetic acid) in analytical
chemistry is overwhelming2 and its large scale use in detergent
formulation and other applications leads to a worldwide market
of several thousands of tons (worldwide use 200 000 tons
per year in 2000).3 Other well known representatives of this
class of compounds are NTA (nitrilotriacetic acid), EGTA
(ethylene-glycol-O,O¢-bis(2-aminoethyl)-N,N,N¢,N¢-tetraacetic
acid), DTPA (diethylenetriamine-N,N,N¢,N¢¢,N¢¢-pentaacetic
acid) and macrocyclic derivatives such as DOTA (1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid).
We chose to focus on an old and well known reaction used to in-
sert an alkyl residue on tertiary amines: the Stevens rearrangement
(Scheme 1).15
Despite the importance of the cited compounds, the litera-
ture reports only few examples of direct modification of these
molecules.4,5 Although a large number of derivatives have been
prepared for different applications, their synthesis always relied
on the assembly of structural frameworks. For example, the
carboxymethyl groups are introduced on a prebuilt backbone
in the last step of the synthesis6–8 or, alternatively, suitably
functionalized/protected carboxymethyl groups are linked on
available simple polyamines,9,10 or preformed synthons are assem-
bled together to give the final ligand.11,12
The large scale and cost-effective availability of the cited ligands
makes them suitable candidates as starting materials for modified
and/or functionalized polyaminopolycarboxylic derivatives.
Long term involvement in the preparation of metal complexes
for diagnostic applications13 prompted us to explore novel proto-
cols for the preparation of modified ligands starting from com-
mercially available polyaminopolycarboxylic ligands. This goal is
Scheme 1
This reaction is a two step protocol involving a preliminary
N-alkylation of the tertiary amine followed by base-induced mi-
gration of an alkyl group on an activated a-position. The Stevens
reaction was recently reviewed16 and although its mechanism is
not yet entirely clarified, much evidence points toward a radical
pathway for the key migration step.17
Particularly interesting is a procedure, employing DBU–K2CO3
in DMF, which performs the alkylation step and the base-induced
migration at the same time.18 Polyaminopolycarboxylic ligands
are well suited substrates for this reaction, as the methylene a to
carboxylic groups represents an “activated” position with respect
to the base induced [1,2]-shift, allowing the latter to occur easily
and regioselectively, as demonstrated by applications reported on
amino acid derivatives.19
aDiSCAFF & DFB Center, Via Bovio 6, I-28100, Novara, Italy. E-mail:
giovenzana@pharm.unipmn.it; Fax: +39-(0)321-375821; Tel: +39-(0)321-
375846
Nevertheless, in our hands the application of such conditions
to a model polyaminopolyester, such as EDTA-tBu4 (1), failed
to give significant yields of the expected products and led to the
isolation of N-alkylated DBU. We decided to modify the reaction
bBracco Imaging spa, Via Ribes 5, I-10010, Colleretto Giacosa (TO), Italy
† Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data. See DOI: 10.1039/c0ob00909a
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conditions, turning to a non-nitrogen base in order to avoid
side reactions and selected the combination K2CO3–18-crown-6.
Concurrently, DMF was substituted with N-methylpyrrolidone
(NMP). Gratifyingly, the reaction worked well in these conditions
and produced the expected alkylation–Stevens rearrangement
products in fair to good yields. The optimal conditions were
found to be 1.5 eq. alkyl halide, 3.0 eq. K2CO3, 0.1 eq. 18-crown-
6 and moderate heating (60 ◦C). Higher temperatures induced
degradation of the intermediate quaternary salt giving unsaturated
by-products, likely from competing Hofmann elimination. On the
other hand, at room temperature the reaction did not proceed
beyond the quaternary salt stage. Higher amounts of the alkylation
agents induced the formation of bis-alkylated species isolated
during the purification. The optimized conditions were then
applied to esters of common polyaminopolycarboxylic ligands
(EDTA, EGTA and DTPA) and selected alkylating agents, such
as allyl and benzyl bromides (Scheme 2).
trace amounts of the other regioisomer. This regioselectivity may
seem surprising, but could be explained by the greater basicity
and nucleophilicity of the central nitrogen atom of diethylen-
etriamine and DTPA,20 which is in this respect preferentially
quaternized.
Simple haloalkanes did not afford alkylated derivatives and the
reaction seems to be limited to reactive halides, at least under
these mild conditions. The products may be easily converted to
the substituted free ligand by simple removal of t-butyl esters
by standard treatment with neat trifluoroacetic acid, complet-
ing this alternative and short protocol to substituted ligands.
Yields are in the range 57–78% for the tandem N-alkylation–
Stevens rearrangement cascade, while the deprotection step is
quantitative.
Conclusions
In conclusion we reported a novel synthetic access to substituted
polyaminopolycarboxylic ligands, relying on a simple procedure
involving a one-pot N-alkylation and Stevens rearrangement.
This protocol avoids the use of strong bases and gives a shorter
access to tailored ligands, paving the way to the wide variety of
applications of their metal complexes, including their conjugation
to biomolecules, macromolecules and surfaces. Efforts are ongoing
to investigate further the protocol, optimizing yields and extending
the array of ligands and alkylating agents involved.
Experimental
General
All chemicals were purchased from Sigma–Aldrich or from Alfa-
Aesar and were used without purification unless otherwise stated.
NMR spectra were recorded on a JEOL ECP 300 (operating
at 7.05 T). ESI mass spectra were recorded on ThermoFinnigan
LCQDeca XP-Plus and melting points (uncorrected) with a Stuart
Scientific SMP3 apparatus.
N-Alkylation–Stevens rearrangement – general procedure
To a solution of t-butyl polyaminopolycarboxylate (1 mmol) in
NMP (10 mL) under dinitrogen atmosphere, K2CO3 (3 mmol),
18-crown-6 (0.1 mmol) and the corresponding alkyl bromide
(1.5 mmol) were sequentially added. The mixture was vigorously
Scheme 2
◦
stirred at 60 C for 3 days. The inorganic salts were filtered off,
The corresponding results are summarized in Table 1. EDTA
and EGTA esters are cleanly monoalkylated in one of the
equivalent a-positions. DTPA gave the product resulting from
alkylation of the a-position of the central arm, along with
diethyl ether (40 mL) was added to the filtrate and the organic
layer was washed with water (3 ¥ 50 mL). The organic layer was
dried over sodium sulfate and evaporated. The crude product was
purified by chromatography column.
Table 1 Reaction yields
Ligand deprotection – general procedure
Substrate
Productsa
The alkylated t-butyl polyaminopolycarboxylate (1 mmol) was
dissolved in 5 mL of trifluoroacetic acid and the reaction was
stirred overnight at rt. Volatiles were evaporated, the crude product
was dissolved in 2 mL of MeOH and precipitated with diethyl ether
(3 ¥ 10 mL) to obtain the deprotected ligand.
1
2
7
3a (65%)
4a (70%)
8a (62%)
3b (62%)
4b (78%)
8b (57%)
a Isolated yields.
680 | Org. Biomol. Chem., 2011, 9, 679–681
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Acknowledgements
Financial supports from Regione Piemonte (Converging Tech-
nologies 2007 – NanoIGT project and PIMP-PIIMDMT Project)
and MIUR (PRIN project) are acknowledged.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 679–681 | 681
©