A new versatile methodology for the synthesis of 4-halogenated-6-diethylcarbamoylpyridine-2-carboxylic acids

Article abstract of DOI:10.1016/S0040-4039(01)00392-6

Convenient syntheses of dipicolinic or chelidamic acid derivatives including 4-X-6-diethylcarbamoyl-pyridine-2-carboxylic acid (X=H, Cl, Br) and 4-chloro-6-(3-oxo-3-phenylpropionyl)pyridine-2-carboxylic acid methyl ester are described. These compounds are important synthons for the synthesis of non-symmetric tridentate aromatic chelating agents as well as for the design of ditopic ligands targeted for the elaboration of functional dimetallic helicates.

Full text of DOI:10.1016/S0040-4039(01)00392-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3089–3091
A new versatile methodology for the synthesis of
4-halogenated-6-diethylcarbamoylpyridine-2-carboxylic acids
Anne-Sophie Chauvin,* Raphae¨l Tripier and Jean-Claude G. Bu¨nzli
Institute of Inorganic and Analytical Chemistry, BCH, University of Lausanne, CH-1015 Lausanne, Switzerland
Received 28 February 2001; revised 5 March 2001; accepted 7 March 2001
Abstract—Convenient syntheses of dipicolinic or chelidamic acid derivatives including 4-X-6-diethylcarbamoyl-pyridine-2-car-
boxylic acid (X=H, Cl, Br) and 4-chloro-6-(3-oxo-3-phenylpropionyl)pyridine-2-carboxylic acid methyl ester are described. These
compounds are important synthons for the synthesis of non-symmetric tridentate aromatic chelating agents as well as for the
design of ditopic ligands targeted for the elaboration of functional dimetallic helicates. © 2001 Elsevier Science Ltd. All rights
reserved.
Benzimidazole based compounds are versatile
molecules that can be conveniently synthesised by a
Phillips reaction.1,2 In particular, they are adequate
ligands for the complexation of whole ranges of d- and
f-transition metal ions. Recently, they have been used
for the construction of two- and three-dimensional
supramolecular networks encapsulating trivalent lan-
thanide ions, Ln(III),3 for the design of tripodal lig-
ands, for the complexation of Ln(III) ions,4,5 in the
synthesis of spin-crossover Fe(II) compounds,6,7 or in
the preparation of bis ligands for the selective complex-
ation of Zn(II).8 Benzimidazole nucleic acid analogues
have been recently synthesised that form duplex com-
plexes with RNA,9 and the condensation of two benz-
imidazole moieties results in the formation of
interesting macrocyclic ligands.10 During the last
decade, we have been tailoring ditopic ligands derived
from bis(benzimidazolyl)pyridine for the design of 4f–4f
and 3d–4f bimetallic functional edifices with lumines-
cent and/or magnetic properties.11–13 Asymmetrically
substituted synthons derived from chelidamic acid (1)
or dipicolinic acid (2) and containing carboxamide
binding units are known to enhance lanthanide
luminescence, but are not easily obtained. Here we
report a new and convenient way of synthesising these
compounds in good yield.
pling between its acylchloride and diethylamine, the
resulting product being hydrolysed in potassium
hydroxide.13 We have now found that adding 1.1 equiv.
of amide anion of diethylamine, readily obtained with
n-butyllithium, to pyridine-2,6-dicarboxylic acid
dimethyl ester (3a)14 in THF gives 6-diethylcarbamoyl-
pyridine-2-carboxylic acid methyl ester (4a),15 which
can easily be hydrolysed into (5a) (Fig. 1).16 This new
strategy produces a much better yield than previously
reported (Table 1) and requires one step less.
Moreover, the same reaction can be extended to func-
tionalising the 4-position of the pyridine, namely for
obtaining 4-chloro-6-diethylcarbamoyl-pyridine-2-car-
boxylic acid methyl ester (4b)17 or 4-bromo-6-diethyl-
carbamoyl-pyridine-2-carboxylic acid methyl ester
(4c).18 These compounds can also be directly
hydrolysed into the corresponding acids (5b) and (5c).
The previously described synthesis of (5b) and (5c)
includes monoesterification of the carboxylic moieties
followed by conversion of the other carboxylic moiety
into acyl chloride, reaction with diethylamine in pres-
ence of triethylamine and a final saponification of the
ester moiety.13 The new synthetic path proposed here is
more convenient, being shorter (three steps instead of
six) and providing substantially better yields than
obtained earlier (Table 1).13
The synthesis of 6-diethylcarbamoyl-pyridine-2-car-
boxylic acid (5a), we previously reported, consisted of a
monoesterification of dipicolinic acid followed by cou-
When using 1.1 equiv. of amide ion and 4-halogenated-
pyridine-2,6-dicarboxylic acid dimethyl ester (3b) or
(3c), no halogen substitution is observed, even when
starting from the very active bromo derivative. In the
previous procedure, bromide was readily substituted in
the presence of chlorinating agents or even in
* Corresponding author. Fax: 41 21 692 3825; e-mail: anne-
sophie.chauvin@icma.unil.ch
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00392-6

3090
A.-S. Chau6in et al. / Tetrahedron Letters 42 (2001) 3089–3091
OH
N
HO
OH
i)
X
N
X
O
O
ii)
(1)
vi)
O
O
O
N
iii)
O
O
O
O
O
H
X = H (3a)
X = Cl (3b)
X= Br (3c)
X = Cl (6b)
HO
OH
N
(2)
X
O
O
iv)
i) X = Cl: PhPOCl2, X = Br: PBr5
ii) MeOH iii) H2SO4, MeOH
X
iv) Et2NH, BuLi, THF v) KOH 1M
vi) PhCOCH3, BuLi, THF
N
OH
N
O
v)
N
N
O
O
O
O
X = H (5a)
X = Cl (5b)
X= Br (5c)
X = H (4a)
X = Cl (4b)
X= Br (4c)
Figure 1.
Table 1. Synthesis of asymmetrically substituted derivatives of dipicolinic and chelidamic acids
Reactant
Nucleophilic agent
Product
This work yield (%)
Literature yield (%)
X=H (2a)
X=Br (3c)
X=Cl (3b)
X=Cl (3b)
X=Cl (3b)
X=Cl (3b)
1.1 equiv. Et2NH, BuLi, THF
1.1 equiv. Et2NH, BuLi, THF
1.1 equiv. Et2NH, BuLi, THF
1.1 equiv. PhCOCH3, BuLi, THF
1.1 equiv. PhCOCH3, NaOEt, EtOH
2.2 equiv. PhCOCH3, BuLi, THF
5a
5c
5b
6b
6b
6b
56.1
28.4
58.0
60.0
50.2
60.8
35.416
16.213
46.713
–
–
–
dichloromethane so that oxallylbromide had to be used
instead of acylchloride, and this should not be left too
long in dichloromethane.13 Despite these precautions
the yield was low. Such a problem is avoided with the
new synthesis (Fig. 1).
no substitution of the chloride or of the other ester
moiety.
In conclusion, the new methodology for the synthesis of
asymmetrically substituted derivatives of dipicolinic
and chelidamic acids proved to be efficient and versatile
since both carboxamide and b-diketone products were
obtained. Thanks to the halo-substituent, these syn-
thons are valuable for producing compounds in which
both the pKa of the carboxylic acid and the light-har-
vesting properties can be modulated. Furthermore, they
can be used to introduce activated groups in ditopic
chelating agents or coupling groups to form covalent
linkages with biological material. Work is under way to
develop such ligands and will be reported elsewhere.
When using an excess of amide ion, simultaneous sub-
stitution of the two diester and chloride functions
occurred.
Among bifunctional chelating agents used for the
enhancement of lanthanide ion luminescence, dipicol-
inic acid, chelidamic acid or b-diketonates proved to be
good candidates.19 For this reason we have applied the
described strategy to the synthesis of b-diketones by
adding acetophenolate (obtained by addition of either
BuLi in THF or sodium ethanolate in ethanol to ace-
tophenone) to 4-chloro-pyridine-2,6-dicarboxylic acid
dimethyl ester (3b). 4-Chloro-6-(3-oxo-3-phenylpro-
pionyl)pyridine-2-carboxylic acid methyl ester (6b)
was obtained as pale yellow crystals (Table 1).20 When
2.2 equiv. of acetophenolate were added instead of
1.1 equiv., the same product (6b) was isolated with
Acknowledgements
This work is supported through grants by the Swiss
National Science Foundation and the Swiss Office for
Science and Education (COST Action D18, contract
C00.0030).

A.-S. Chau6in et al. / Tetrahedron Letters 42 (2001) 3089–3091
3091
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their corresponding acids.
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14. General procedure: an n-butyllithium solution 1.6 M in
hexane (2.39 mmol) is added slowly under a nitrogen
atmosphere to a mixture of diethylamine (2.39 mmol) in
freshly distilled tetrahydrofuran (50 mL). After 10 min
stirring, this yellow mixture is added very slowly under
controlled atmosphere and with vigorous stirring to a
solution of the 4-X-2,6-dimethylpyridindicarboxylate
(X=H, Cl, Br) (2.17 mmol) in tetrahydrofuran (20 mL).
The mixture becomes brown and is stirred at room
temperature for 12 h. After solvent evaporation, a white–
.