Synthesis of novel derivatives of pyridine-2,6-dicarboxylic acid

Article abstract of DOI:10.1080/00397910600634381

Two series of novel derivatives of pyridine-2,6-dicarboxylic acid with potential as polydentate ligands were synthesized from pyridine-2,6-dicarboxylic acid. All new compounds were characterized by NMR, MS, IR, and EA. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600634381

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Synthesis of Novel Derivatives of
Pyridine‐2,6‐dicarboxylic Acid
Rui‐ren Tang a , Qiang Zhao a , Zi‐er Yan a & Yi‐ming Luo a
a School of Chemistry and Chemical Engineering, Central South University,
Changsha, China
Version of record first published: 20 Aug 2006.
To cite this article: Rui‐ren Tang , Qiang Zhao , Zi‐er Yan & Yi‐ming Luo (2006): Synthesis of Novel
Derivatives of Pyridine‐2,6‐dicarboxylic Acid, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:14, 2027-2034
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Synthetic Communicationsw, 36: 2027–2034, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600634381
Synthesis of Novel Derivatives of
Pyridine-2,6-dicarboxylic Acid
Rui-ren Tang, Qiang Zhao, Zi-er Yan, and Yi-ming Luo
School of Chemistry and Chemical Engineering,
Central South University, Changsha, China
Abstract: Two series of novel derivatives of pyridine-2,6-dicarboxylic acid with
potential as polydentate ligands were synthesized from pyridine-2,6-dicarboxylic
acid. All new compounds were characterized by NMR, MS, IR, and EA.
Keywords: Ligands, pyridine-2,6-dicarboxylic, synthesis
There has been steadily increasing interest in lanthanide coordination
chemistry over the past two decades, essentially because of its potential appli-
cations in biology and medicine for analytical and diagnostic purposes such as
time-resolved fluorescence immunoassay.[1,2] One challenge in the design of
functional lanthanide-containing coordination compounds is the need for
precise control of the Ln(III) inner coordination sphere, because a varying
degree of nondirectional bonding is possible. Derivatives of pyridine-2,6-
dicarboxylic acid, also known as dipicolic acid or DPA, are ubiquitous in
biology[2] and have been found to be promising ligands in time-resolved
fluorescence immunoassay. This is due to the stability of their lanthanide(III)
complexes, and their strong fluorescence intensity with relatively long exci-
tation lifetimes, which make the luminescent probe replaced radioimmuno-
assay (RIA). Much work has been devoted to designing polydentate ligands
that can complex with lanthanide(III), resulting in luminescent complexes
that can act as efficient light-conversion molecular devices (LCMDs).[3]
These devices allow energy absorbed by the ligands to be transferred to the
Address correspondence to Rui-ren Tang, School of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, China. E-mail: trr@mail.
csu.edu.cn
2027

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R.-r. Tang et al.
emitting metal ions, thus increasing the absorption UV cross section. Lamture
et al. have designed a series of 4-substituted analogues of pyridine-2,6-dicar-
boxylic acid and noted that a 4-Cl substituent increases the energy transfer
efficiency in DPA complexes of terbium(III).[4] However, there have been
no reported syntheses of 4-hydroxyalkyl DPA derivatives, from which
many multifunctional DPA derivatives could be prepared. In this article, we
propose a simple strategy for introducing a hydroxymethyl group in the
4-position of DPA, thus opening way for the preparation of more elaborate
ligands by substitution with nucleophiles containing strong coordinating
groups, such as iminodiacetic acid.
Our synthetic strategy is outlined in Scheme 1. Esterification of DPA (1)
with acidic methanol afforded DPA dimethyl ester 2, which underwent direct
nucleophilic aromatic substitution by a carbon-centered radical[5] to give the
4-hydroxymethylated derivative 3[6] in moderate yield. The key intermediate
3 was converted to the corresponding iodide 5 under standard conditions, via
the tosylate 4, in good overall yield. Treatment of 5 with methyl acetoacetate
under basic conditions gave the triester 6, and similar reactions of 5 with
dimethyl iminodiacetate and dimethyl malonate yielded the esters 8 and 10
respectively. Hydrolysis of the methyl esters 6, 8, and 10 afforded three
novel DPA ligands, namely the acids 7, 9, and 11. In addition, hydrolysis of
4-hydroxymetbyl DPA 3 gave the diacid 12, and aminolysis of 3 afforded
the novel diamide 13.
The amide functional group is found throughout nature in the primary
structure of proteins and also plays an important role in coordination
chemistry.[2] In this study, two polydentate pyridine diamide ligands were
prepared by treating pyridine-2,6-dicarboxylic acid chloride (15) with
pyrazole (14) and aminopyridine (17), as shown in Scheme 2. The resulting
ligands 16 and 18 bear multiple N and O donor atoms in a large conjugated
plane, which can protect metal ions from their environment when the
complexes are formed, and in their fluorescence probe the shielding effect
considerably reduces nonradiative deactivation processes.[7]
In summary, we have presented facile methods for the preparation of both
4-hydroxymethyl pyridine-2,6-dicarboxylic acid and polydentate pyridine-
2,6-diamide derivatives of DPA from pyridine-2,6-dicarboxylic acid (1).
EXPERIMENTAL
General Information
IR spectra were measured on a Perkin-Elmer 1600 FT-IR spectrometer as
KBr discs. MS was carried out on a HP-5988A GC-MS spectrometer. All
nuclear magnetic resonance (NMR) spectra were recorded at 297 K with
Varian 400-MHz spectrometer. Chemical shifts are reported as in ppm
relative to TMS fixed at 0 ppm. Elemental analysis with C, H, N were

Novel Derivatives of Pyridine-2,6,-dicarboxylic Acid
2029
Scheme 1.

2030
R.-r. Tang et al.
Scheme 2.
performed on a Perkin-Elmer 2400 elemental analyzer. Reactions were
monitored by TLC, using precoated silica gel 60 F254 with detection under
ultraviolet light.
The diester 2 was prepared according to Ref. 5, and the pyrazole 14 was
prepared according to Ref. 7.
4-((bis(Carboxymethyl)imino)methyl)-pyridine-2,6-dicarboxylic
Acid (9)
.
Solutions of FeSO4 7H2O (a saturated solution of 10mL in water) and 30%
H2O2 (70 mmol) were added dropwise to a vigorously stirred suspension of
pyridine-2,6-dicarboxylic acid dimethyl ester (2) (1.95 g, 10mmol) in
methanol (10 mL) and 30% H2SO4 (10 mL), maintaining a reaction temperature
of 15–308C by control of the addition rate. The mixture was stirred for 10min
after the addition was complete, and K2CO3 was added to adjust the acidity of
the solution to pH 6–7. After the solid was filtered off, the filtrate was extracted
with ethyl acetate (5 ꢀ 20mL) and the organic extracts were dried (Na2SO4)
and concentrated under reduced pressure. Flash chromatography eluting with
1 : 1 ethyl acetate–petroleum ether gave 3 as a colorless solid.
A solution of p-toluenesulphonyl chloride (6.88g, 36.1 mmol) in CH2Cl2
(25 mL) at 08C was added to 4-hydroxymethyl-pyridine-2,6-dicarboxylate 3
(5.81g, 25.8 mmol) in CH2Cl2 (40 mL). After stirring at 08C for 20 min,
triethylamine (10 mL) was added dropwise in three portions at 20-min
intervals. The mixture was stirred at 08C for 15 min and at room temperature
for a further 15 min. The reaction was diluted with ethyl acetate, and the
organic phase was washed with water (3 ꢀ 20 mL) and 3% HCl
(3 ꢀ 20 mL), dried (MgSO4), and concentrated under reduced pressure.
Recrystallization from ether afforded the tosylate 4 as colorless needles.

Novel Derivatives of Pyridine-2,6,-dicarboxylic Acid
2031
The tosylate 4 (7.58 g, 20 mmol) was added to a solution of NaI (4.50 g,
30 mmol) in acetone (250 mL), and the reaction mixture was heated at reflux
for 2.5 h. The cooled solution was diluted with ethyl acetate (550 mL), and the
organic phase was washed with water (3 ꢀ 150 mL), 3% HCl (3 ꢀ 120 mL),
and 5% Na2SO3 solution (2 ꢀ 50 mL). The organic extract was dried
(Na2SO4) in darkness and concentrated under reduced pressure to give the
crude iodide 5.
HN(CH2COOMe)2 (0.58 g, 3.5 mmol) was added to a solution of the
iodide 5 (0.60 g, 1.7 mmol) in THF (5 mL), and the mixture was stirred in
darkness at room temperature for 12 h. The solvent was evaporated under
reduced pressure, and the residue was washed with water (3 ꢀ 10 mL) and
5% Na2S2O3 solution (10 mL). The organic phase was dried (Na2SO4) and
concentrated under reduced pressure to give the crude product, which was
recrystallized from ethanol to afford the dimethyl ester 8 as a colorless solid.
A 30% NaOH solution (6 mL) was added to the diester 8 (1.8 g, 5.0 mmol)
in methanol (50 mL), and the mixture was stirred at room temperature for
24 h. Evaporation of the solvent gave a yellow solid, which was purified
using a 732 cation resin column to give the diacid 9 as a colorless solid.
Diacids 7 and 11 were prepared from 6 and 8 using the same method as
for 9.
General Procedure for the Synthesis of Amide Derivatives of DPA
The amine 14 (3 mmol) and triethylamine (3 mmol) in anhydrous THF
(20 mL) were added to a solution of 2,6-pyridinediformyl chloride 15
(1.5 mmol) in anhydrous THF (60 mL). The mixture was heated at reflux for
about 6 h, when TLC indicated that the reaction was complete. After the sus-
pension was cooled to room temperature, the precipitate was removed fil-
tration and the filtrate was concentrated to about 8 mL. The resulting solid
was filtered off to give the crude product, which was recrystallized from
1 : 1 CHCl3–MeOH to give the diamide 16.
The diamide 18 was similarly prepared from the acid chloride 15 and the
pyrazole 17.
Data
Compound 3.[6] Yield: 41%. Mp 154–1588C. IR (KBr): n 3485, 3079, 3014,
1
2959, 1723, 1705, 1609, 1453, 1226, 1158, 984 cm21. H NMR (400 MHz,
CDCl3): d 8.23 (s, 2H, Py-3, 5-H), 4.91 (s, 2H, CH2), 4.03 (s, 6H, OCH3).
m/z (FAB): 225 (Mþ). Elemental analysis: calcd. for C10H11NO5: C, 53.33;
H, 4.92; N, 6.22. Found: C, 53.61; H, 4.92; N, 6.18.
1
Compound 4. Yield: 81%. Mp 136–1378C. H NMR (300 MHz, CDCl3): d
8.16 (s, 2H, Py-3, 5-H), 7.84–7.81 (d, J ¼ 8.2 Hz, 2H, Ar-H), 7.37–7.34

2032
R.-r. Tang et al.
(d, J ¼ 8.2 Hz, 2H, Ar-H), 5.16 (s, 2H, CH2), 4.02 (s, 6H, OCH3), 2.45 (s, 3H,
Ar-CH3). Elemental analysis: calcd. for C17H17NO7S: C, 53.82; H, 4.52; N,
3.69. Found: C, 53.91; H, 4.52; N, 3.68.
1
Compound 5. Yield: 78%. Mp 148–1508C. H NMR (300 MHz, CDCl3): d
8.28 (s, 2H, Py-3, 5-H), 4.45 (s, 2H, CH2I), 4.04 (s, 6H, OCH3). Elemental
analysis: calcd. for C10H10INO4: C, 35.84; H, 3.01; N, 4.18. Found: C,
35.88; H, 2.98; N, 4.15.
Compound 6. Yield: 61%. Mp 76–788C. IR (KBr): n 3428, 3081, 2962, 1742,
1
1723, 1611, 1566, 1450, 1367, 1158, 1001, 898 cm21. H NMR (400 MHz,
CDCl3): d 8.14 (s, 2H, Py-3, 5-H), 4.02 (s, 6H, OCH3), 3.94 (t, J ¼ 7.2 Hz,
1H, CH), 3.73 (s, 3H, OCH3), 3.30 (d, J ¼ 7.1 Hz, 2H, CH3), 2.27 (s, 3H,
COCH3). 13C NMR (100 MHz, CDCl3): d 200.4, 168.5, 164.9, 150.6, 148.4,
128.4, 59.4, 53.2, 52.9, 32.6, 29.5. m/z (FAB): 324 (Mþ þ 1). Elemental
analysis: calcd. for C15H17NO7: C, 55.73; H, 5.30; N, 4.33. Found: C,
55.91; H, 4.32; N, 4.26.
1
Compound 7. Yield: 97%. Mp 187–1898C (decomp). H NMR (400 MHz,
D2O): d 8.03 (s, 2H, Py-3, 5-H), 3.84 (t, J ¼ 6.9 Hz, 1H, CH), 3.68
(d, J ¼ 7.0 Hz, 2H, CH2), 2.33 (s, 3H, COCH3). Elemental analysis:
calcd. for C12H11NO7: C, 51.25; H, 3.94; N, 4.98. Found: C, 51.32; H, 4.02;
N, 4.94.
Compound 8. Yield: 95%. Mp 95–978C. IR (KBr): n 2996, 2958, 1746,
1732, 1720, 1439, 1417, 1214, 1162, 1014, 779, 735 cm21 1H NMR
.
(400MHz, CDCl3): d 8.03 (s, 2H, Py-3, 5-H), 4.11 (s, 2H, CH2), 4.03 (s, 6H,
OCH3), 3.72 [s, 6H, (OCH3)2], 3.58 (s, 4H, NCH2). 13C NMR (100MHz,
CDCl3): d 171.1, 165.2, 151.7, 148.6, 127.8, 56.6, 54.5, 53.2, 51.8. m/z
(FAB): 368 (Mþ), 337 (M-CH3O), 309 (100%, M-CH3O-CO), 209, 150.
Elemental analysis: calcd. for C16H20N2O8: C, 52.17; H, 5.47; N, 7.61.
Found: C, 52.32; H, 5.42; N, 7.84.
Compound 9. Yield: 98%. IR (KBr): 3461, 3131, 1724, 1710, 1637, 1604,
1
1560, 879, 726 cm21. H NMR (400 MHz, DMSO-d6): d 12.50 (br s, 4H,
COOH, exchange in D2O), 8.29 (s, 2H, Py-3, 5-H), 4.04 (s, 2H, CH2), 3.48
(s, 4H, –NCH2). 13C NMR (100 MHz, DMSO-d6): d 172.1, 165.5, 152.4,
148.0, 126.9, 56.8, 54.1. Elemental analysis: calcd. for C12H12N2O8: C,
46.16; H, 3.87; N, 8.97. Found: C, 46.31; H, 3.92; N, 8.94.
Compound 10. Yield: 49%. 1H NMR (400 MHz, CDCl3): d 8.17 (s, 2H, Py-3,
5-H), 4.16 (s, 6H, OCH3), 3.87 (t, J ¼ 7.1 Hz, 1H, CH), 3.61 (s, 6H, OCH3),
3.09 (d, J ¼ 7.1 Hz, 2H, CH2). m/z (FAB): 340 (Mþ þ 1), 308 (M-OCH3), 281
(M-COOCH3 þ 1). Elemental analysis: calcd. for C15H17NO8: C, 53.10; H,
5.05; N, 4.13. Found: C, 52.91; H, 5.06; N, 4.16.

Novel Derivatives of Pyridine-2,6,-dicarboxylic Acid
2033
1
Compound 11. Yield: 97%. H NMR (400 MHz, D2O): d 8.15 (s, 2H, Py-3,
5-H), 3.68 (t, J ¼ 7.0 Hz, 1H, CH), 3.47 (d, J ¼ 7.0 Hz, 2H, CH2).
Elemental analysis: calcd. for C11H9NO8: C, 46.65; H, 3.20; N, 4.95.
Found: C, 46.31; H, 3.22; N, 4.98.
Compound 12. Yield: 100%. 1H NMR (400 MHz, D2O): d 8.28 (s, 2H, Py-3,
5-H), 4.86 (s, 2H, CH2). Elemental analysis: calcd. for C8H7NO5: C, 48.74; H,
3.58; N, 7.10. Found: C, 48.59; H, 3.60; N, 7.13.
Compound 13. Yield: 98%. Mp 365–3688C. IR (KBr): n 3423, 3313, 1698,
1666, 1602, 1404, 1335, 1063, 1114, 678 cm21. 1H NMR (400 MHz, DMSO-
d6): d 8.86 (s, 2H, NH2), 8.15 (s, 2H, Py-3, 5-H), 7.68 (s, 2H, NH2), 5.62
(s, 1H, OH), 4.69 (s, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 165.4,
155.1, 148.9, 121.1, 61.4. Elemental analysis: calcd. for C8H9N3O3: C,
49.23; H, 4.65; N, 21.53. Found: C, 49.22; H, 4.63; N, 21.87.
Compound 16. Yield: 32%. Mp 208–2098C. IR (KBr): n 2901 (br COOH),
1700, 1698, 1671, 1666, 1573, 1557, 1521, 1450, 1367 cm21 1H NMR
.
(400 MHz, CDCl3): d 8.36 (s, 2H, Py-3, 5-H), 8.11 (t, J ¼ 7.3 Hz, 1H, Py-4-
H), 6.31 (s, 2H, Pyraz.), 2.73 (d, 6H, CH3) m/z (FAB): 383 (Mþ).
Elemental analysis: calcd. for C17H13N5O6: C, 53.27; H, 3.42; N, 18.27.
Found: C, 53.72; H, 3.34; N, 18.34.
Compound 18.[8] Yield: 72%. Mp 120–1238C. IR (KBr): n 3451, 3224, 1741,
1676, 1528, 1453, 1374 cm21. 1H NMR (400 MHz, CDCl3): d 10.50 (s, N–H),
8.70 (t, 1H, Py-4-H), 8.50 (s, 2H, Py-3, 5-H), 8.30 (2H, aminoPy-60-H), 7.60 (2H,
aminoPy-50-H), 7.40 (2H, aminoPy-40-H), 2.40 (s, 6H, CH2) (should include 2
d.p. for the chemical shifts). 13C NMR (100 MHz, CDCl3): 161.8, 149.2,
146.1, 140.6, 139.6, 129.6, 122.4, 18.3. Elemental analysis: calcd. for
C20H18N4O2: C, 69.35; H, 5.24; N, 16.17; Found: C, 69.15; H, 5.31; N, 15.98.
ACKNOWLEDGMENTS
Financial support from National Natural Science Foundation of China (No.
50573019) is gratefully acknowledged.
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