Free-radical approach to 4-substituted dipicolinates

Article abstract of DOI:10.1002/ejoc.200400637

Dimethyl pyridine-2r6-dicarboxylate was selectively substituted through free-radical reactions. The substitution involves the generation of free radicals through Fenton-type reactions, followed by hydrogen abstraction from aldehydes or alcohols. The resul

Full text of DOI:10.1002/ejoc.200400637

FULL PAPER
Free-Radical Approach to 4-Substituted Dipicolinates
Rimma Shelkov[a] and Artem Melman*[a]
Keywords: Heterocycles / Acylation / Alkylation / Radical reactions
Dimethyl pyridine-2,6-dicarboxylate was selectively substi-
tuted through free-radical reactions. The substitution in-
volves the generation of free radicals through Fenton-type
reactions, followed by hydrogen abstraction from aldehydes
or alcohols. The resultant carbon-centered acyl, alkyl, or hy-
droxyalkyl free radicals regioselectively attack protonated
dimethyl pyridine-2,6-dicarboxylate at position 4, yielding
the corresponding dimethyl 4-acyl-, 4-alkyl-, and 4-(hy-
droxyalkyl)pyridine-2,6-dicarboxylates.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
shira coupling,[4,11] Suzuki coupling,[6] the Heck reaction,[5]
or reactions with stabilized enolates.[12]
Introduction
Pyridine-2,6-dicarboxylic (dipicolinic) acid and its deriv-
atives are highly useful tridentate ligands. Pyridine-2,6-di-
carboxylic acid forms nine-coordinating luminescent com-
plexes with lanthanides, providing high quantum yields of
phosphorescence[1] and used as luminescent tags, labels, and
barcodes.[2] Chiral pybox (2,6-bis-oxazolidinopyridine) li-
gands, which can be easily prepared from esters or the chlo-
roanhydride of pyridine-2,6-dicarboxylic acid through the
use of commercially available chiral amino alcohols, have
found numerous applications in transition metal-catalyzed
asymmetric syntheses.[3]
Despite the simplicity of the preparation of tridentate li-
gands based on pyridine-2,6-dicarboxylic acid, fabrication
of complex systems based on its derivatives, such as concave
pyridines,[4] peptide-incorporated metal chelators,[5] inhibi-
tors of farnesyltransferase,[6] luminescent probes,[7] or poly-
mer-bound pybox ligands,[8] necessitates derivatization of
the pyridine ring. Consequently, substantial efforts have
been concentrated on the preparation of functionalized pyr-
idine-2,6-dicarboxylic acid derivatives. Instead of the cheap
and abundant pyridine-2,6-dicarboxylic acid, however,
these syntheses have had to be based on 4-halo-pyridine-
2,6-dicarboxylates, prepared from expensive chelidamic
acid (4-oxo-1,4-dihydro-2,6-pyridine dicarboxylic acid).[9]
Existing methods of preparation of 4-heteroatom-function-
alized pyridine-2,6-dicarboxylic acid derivatives involve the
replacement of the 4-halogen atom with different N- and
O-nucleophiles.[10] Replacement of the 4-halogen atom with
carbon-based substituents has been achieved through palla-
dium-catalyzed couplings with vinyltributyltin,[8] Sonoga-
Direct functionalization of pyridine-2,6-dicarboxylates
could be an attractive alternative to these syntheses based
on chelidamic acid. Such a functionalization cannot be per-
formed by conventional substitution reactions, however, be-
cause of the resistance of the pyridine ring in pyridine-2,6-
dicarboxylic acid derivatives to electrophilic and nucleo-
philic attacks.
Free radical substitutions in aromatic systems have been
known for a long time but are relatively rarely used in pre-
parative synthesis.[13] The regioselectivity of free-radical
substitution in monosubstituted benzenes is generally low,
although strong –E substituents, such as cyano, ester, and
nitro groups, direct the substitution to the ortho and para
positions.[14]
Minisci and co-authors were first to discover that free-
radical substitution with nucleophilic carbon-centered radi-
cals in protonated pyridine and quinoline systems proceeds
regioselectively with almost exclusive substitution at posi-
tions 2 and 4.[15] Treatment of organic peroxides with
FeII[16] and TiIII[17] reagents, followed by hydrogen or iodine
transfer, as well as oxidative silver-catalyzed decarboxyl-
ations,[18] were used for the generation of the carbon-cen-
tered free radicals. The Minisci reaction was also success-
fully extended to other nitrogen-containing heteroarenes.
The presence of electron-withdrawing substituents in het-
eroaromatic rings was reported to increase the substitution
rates substantially,[19] making the Minisci reaction poten-
tially suitable for functionalization of electron-poor system
such as pyridine-2,6-dicarboxylic acid derivatives.
Minisci’s methodology, in contrast to the more com-
monly used tributyltin-mediated reductive free-radical reac-
tions,[20] requires at least equimolecular quantities of hydro-
gen or alkyl peroxide. However, the generation of free radi-
cals through Fenton-type reactions relies on cheap and en-
[a] Department of Organic Chemistry, The Hebrew University of
Jerusalem,
Jerusalem 91904, Israel
E-mail: amelman@chem.ch.huji.ac.il
Eur. J. Org. Chem. 2005, 1397–1401
DOI: 10.1002/ejoc.200400637
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R. Shelkov, A. Melman
FULL PAPER
vironmentally friendly reagents, making them more suitable preted, however, by taking account of the low basicity of
for large-scale syntheses.
pyridine-2,6-dicarboxylates,[22] which results in very low
In this paper we report on the derivatization of pyridine- equilibrium concentrations of the corresponding cations 1
2,6-dicarboxylic acid derivatives through free radical substi- in the reaction mixture.
tution reactions that were found to proceed differently from
Performing the reaction in 30% water/H2SO4 as solvent
literature examples. These reactions produce various 4-car- (Scheme 2, procedure A) provided the necessary highly
bon-substituted derivatives that may be useful precursors acidic conditions to enforce the protonation of dimethyl
for the preparation of complex 4-functionalized pyridine- pyridine-2,6-dicarboxylate, and the designed free-radical
2,6-dicarboxylic acid- and pybox-type ligands.
substitutions then indeed took place. These reactions pro-
ceeded with complete regioselectivity and no detectable
amounts of isomeric products were observed, despite the
presence of two electron-withdrawing methoxycarbonyl
groups, known to favor 3-substitution.[14,23]
Results and Discussion
Our approach to free-radical derivatization of pyridine-
2,6-dicarboxylates (Scheme 1) involved the generation of
oxygen-centered radicals through Fenton-type reactions,
followed by abstraction of a hydrogen atom from aldehydes
and alcohols by the produced oxygen-centered radicals. The
resulting nucleophilic carbon-centered radicals were ex-
pected, analogously to reports by Minisci,[21] to attack pro-
tonated dimethyl dipicolinate (1). Subsequent in situ C-de-
protonation of resultant cation-radicals 2 and oxidation of
the intermediate radicals 3 with Fe3+ were intended to yield
4-substituted dipicolinate derivatives of type 4.
Scheme 2.
Instead of the expected ketones of type 7, however, the
only isolated reaction products were 4-alkyl derivatives of
type 8. The formation of these products can be explained
by the decarbonylation of the initially formed acyl radicals
of type 5, followed by the free radical attack of the resultant
alkyl radicals of type 6 on the protonated dipicolinate 1.
Decarbonylation in free radical substitutions had pre-
Scheme 1.
Our initial attempts to perform the derivatization of di- viously been reported in similar reactions of heteroaromatic
methyl pyridine-2,6-dicarboxylate were carried out in aque- substitution only for acyl radicals possessing quaternary –
ous solutions acidified with 1–5 equiv. of sulfuric acid, with but not tertiary or secondary – α-carbon atoms,[24] and even
use of the H2O2/FeSO4 system for generation of hydroxy in this case the percentage of the decarbonylated product
radicals and aliphatic aldehydes as hydrogen donors. None was very small. It could be assumed that despite the applied
of these attempts produced any substitution product, re- highly acidic reaction media, the concentration of the pro-
sulting in complete recovery of the starting material. These tonated form of dimethyl pyridine-2,6-dicarboxylate still re-
results were unexpected, as literature data[19] report en- mained low, thus decreasing the bimolecular free-radical
hanced reactivity of acyl-substituted azaaromatic com- addition rates. As a result, the competing intramolecular
pounds toward free-radical attacks. The observed very low decarbonylation pathway prevailed, resulting in the forma-
reactivity of pyridine-2,6-dicarboxylic system can be inter- tion of alkyl radicals of type 6 and eventually in the forma-
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Free-Radical Approach to 4-Substituted Dipicolinates
FULL PAPER
tion of 4-alkyl derivatives 8a and 8d. No measurable transformation to produce a number of oligomeric prod-
amounts of substitution products 7/8b or 7/8c were ob- ucts.[27]
served in reactions with benzaldehyde and acetaldehyde un-
Although chromatographic separation of the reaction
der these reaction conditions, which is probably related to product 9 from the starting dimethyl pyridine-2,6-dicarbox-
very low decarbonylation rates of acyl radicals 5b and 5c.[25] ylate is straightforward, it may give rise to practical prob-
The chemoselectivity of the reaction can be changed by lems at multigram scales. To bypass chromatographic sepa-
further increasing the acidity of the reaction media. Be- ration, an alternative purification procedure involving si-
cause of the low solubility of FeSO4 in acetic acid, pro- lylation of the crude reaction mixture was elaborated. Prep-
cedure B provided less than 100% conversions (no optimi- aration of other functionalized pyridine-2,6-dicarboxylates
zation of the reaction conditions was carried out).[26] Treat- from alcohol 9 can easily be done through its conversion
ment of dimethyl pyridine-2,6-dicarboxylate with aliphatic into 4-iodomethyl and 4-formylpyridine-2,6-dicarboxylates
and aromatic aldehydes in a mixture of acetic acid and 66% by existing methodologies.
sulfuric acid as solvent and with a tBuOOH/FeSO4 system
Similar free radical reactions with alcohols such as etha-
for the generation of radicals (procedure B) produced an nol, butanol, butane-1,4-diol, and 3-acetoxypropanol failed
outcome substantially different to that of procedure A. In- to provide any appreciable yields of monomeric substitution
stead of the 4-ethylpyridine 8a, the predominant reaction products. This could have been expected, as the free radical
product was the 4-propionylpyridine 7a. The same free-rad- substitution competes with the oxidation of α-hydroxyalkyl
ical acylation also proceeded successfully with benzalde- radicals by Fe3+. The oxidation rates for reactions with ali-
hyde and acetaldehyde, both of which had failed to provide phatic alcohols are substantially larger than that for meth-
any substitution products in procedure A.
anol. This oxidation is the most probable reason for unex-
Free-radical reactions were also used for direct introduc- pected results in an analogous FeSO4/H2O2-initiated reac-
tion of 4-hydroxyalkyl substituents. Treatment of dimethyl tion between dimethyl pyridine-2,6-dicarboxylate and an
pyridine-2,6-dicarboxylate with slowly added aqueous solu- excess of propane-1,3-diol, as the major isolable reaction
tions of FeSO4 and H2O2 in aqueous methanol produced product was found to be the 2-hydroxyethyl pyridine 11
the 4-hydroxymethyl-substituted pyridine 9 (Scheme 3) in (Scheme 4).
30% yield (48% recovery-based). The reaction mechanism
involves hydrogen transfer from methanol to initially
formed hydroxy radicals, followed by the free-radical attack
of the resultant nucleophilic hydroxymethyl radicals on the
protonated pyridine 1, as shown in Scheme 1. Subsequent
in situ deprotonation and oxidation of the intermediate rad-
ical of type 3 (R = CH2OH) with Fe3+ produced the 4-
hydroxymethyl-substituted pyridine 9.
Scheme 4.
Most probably, the mechanism of formation of the
hydroxyethyl-substituted pyridine 11 includes an attack of
the 2-hydroxyethyl radical 17 on the protonated ester 1. A
Scheme 3.
Acceptable yields of the 4-hydroxymethyl-substituted possible reaction mechanism for the formation of the 2-
pyridine 9 could be obtained only below 50% conversions. hydroxyethyl pyridine 11 could involve hydrogen abstrac-
Attempts to achieve 100% conversion provided lower yields tion from propane-1,3-diol by Fenton-generated hydroxy
of 9, accompanied by unidentified polymeric byproducts. radicals. Subsequent oxidation of the resultant radical 13
The formation of polymeric products can be expected by with Fe3+ cations[21] should provide 3-hydroxypropanal 14,
taking account of the ability of alcohol 9 to undergo hydro- which should be capable of undergoing a second hydrogen
gen abstraction with hydroxy radicals. Such a reaction transfer followed by decarbonylation, in analogy to the re-
should produce a highly stabilized and nucleophilic α-hy- actions shown in Scheme 2. Because neither butanol nor 3-
droxybenzylic radical 10, which could undergo further acetoxypropanol provide free-radical substitution products
Eur. J. Org. Chem. 2005, 1397–1401
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R. Shelkov, A. Melman
FULL PAPER
3.07 (sept., J = 7 Hz, 1 H), 4.02 (s, 6 H), 8.18 ppm (s, 2 H). IR
under similar reaction conditions, the second hydroxy
group clearly participates in this process.
(film): ν = 646, 908, 1217, 1250, 1266, 1332, 1360, 1443, 1717 cm–1.
˜
MH+ 238.1 calcd. 238.1. C12H15NO4 (237.25): found: C 60.63, H
6.27, N 5.83; calcd.: C 60.75, H 6.37, N 5.90.
In conclusion, we have demonstrated a new, one-step ap-
proach for the regiospecific preparation of 4-alkyl- and 4-
acylpyridine-2,6-dicarboxylates by free-radical methodol-
ogy involving the generation of oxygen-centered radicals
through Fenton-type reactions, abstraction of hydrogen
from aromatic and aliphatic aldehydes, and free-radical
substitution of protonated dimethyl pyridine-2,6-dicarbox-
ylate by the resultant acyl radicals. The substitution can be
carried out in highly acidic solution and is accompanied by
complete or partial decarbonylation of acyl radicals. The
decarbonylation can be controlled by changing the acidity
of reaction media. The same methodology was also used
for the preparation of 4-(hydroxymethyl)- and 4-(2-hydroxy-
ethyl)pyridine-2,6-dicarboxylates by use of methanol and
propane-1,3-diol for the generation of carbon-centered rad-
icals.
General Procedure B, for Preparation of Dimethyl 4-Acylpyridine-
2,6-dicarboxylates 7a–c: A solution of tBuOOH (4.50 g, 50 mmol)
in acetic acid (3 mL) was added dropwise over 5 min with vigorous
stirring to a solution of dimethyl pyridine-2,6-dicarboxylate (4.88 g,
25 mmol) in a mixture of acetic acid (6 mL), water (2 mL), conc.
sulfuric acid (4 mL), FeSO4·7H2O (6.95 g, 25 mmol), and an alde-
hyde (50 mmol). The reaction mixture was stirred for an additional
2 min, poured into water, and extracted with ethyl acetate. The
ethyl acetate solution was washed with brine, dried, and evapo-
rated, and the residue was separated by flash chromatography to
yield compounds 7a–c along with starting dimethyl pyridine-2,6-
dicarboxylate, and (for 7a) minor amounts of 4-ethylpyridine 8a.
Dimethyl 4-Propionylpyridine-2,6-dicarboxylate (7a): This com-
pound was prepared from dimethyl pyridine-2,6-dicarboxylate
(0.39 g) and propanal (0.23 g). Chromatography with hexane/ethyl
acetate (7:3 to 1:1) provided the title compound (0.17 g, 34%),
along with recovered dimethyl pyridine-2,6-dicarboxylate (85 mg,
22%) and 8a (54 mg, 12%). 1H NMR (300 MHz, CDCl3): δ = 1.27
(t, J = 7.1 Hz, 3 H), 3.09 (q, J = 7.1 Hz, 2 H), 4.04 (s, 6 H),
8.69 ppm (s, 2 H). 13C NMR (75 MHz): δ = 7.5, 32.6, 53.4, 125.4,
Experimental Section
All reagents were commercial C.P. grade and were not additionally
purified unless otherwise stated. Dimethyl pyridine-2,6-dicarboxyl-
ate was synthesized from pyridine-2,6-dicarboxylic acid by the pub-
lished procedure. tert-Butyl hydroperoxide contained 20% of di-
tert-butyl peroxide. Dropwise addition was carried out with a sy-
ringe pump. Flash chromatography was performed on 230–400
mesh Silica gel 60 supplied by Merck. Elementary microanalyses
were performed in the Laboratory of Microanalysis of the Hebrew
University. Electrospray mass spectra of compounds were recorded
on a Finnegan LCQ Classic mass spectrometer in dichloromethane
solutions in the presence of 5% of MeSO3H. 1H NMR spectra
were recorded in CDCl3 on Bruker AMX 300 and DRX 400 NMR
spectrometers. Chemical shifts (δ) are measured in ppm using resid-
ual solvent peak for calibration.
145.3, 149.5, 164.5, 198.1 ppm. IR (film): ν = 774, 999, 1152, 1212,
˜
1246, 1437, 1697, 1749 cm–1. MH+ 252.1 calcd. 252.1. C12H13NO5
(251.24): found: C 56.97, H 5.19, N 5.29; calcd.: C 57.37, H 5.22,
N 5.58.
Dimethyl 4-Acetylpyridine-2,6-dicarboxylate (7b): This compound
was prepared from dimethyl pyridine-2,6-dicarboxylate (0.39 g)
and acetaldehyde (0.18 g). Chromatography with hexane/ethyl ace-
tate (7:3 to 1:1) provided the title compound (0.25 g, 52%), along
with recovered dimethyl pyridine-2,6-dicarboxylate (0.10 g, 26%).
1H NMR (300 MHz, CDCl3): δ = 2.73 (s, 3 H), 4.06 (s, 6 H),
8.70 ppm (s, 2 H). 13C NMR (75 MHz): δ = 26.8, 53.3, 53.2, 125.4,
145.2, 149.5, 164.8, 198.2 ppm. IR (film): ν = 997, 1145, 1165, 1245,
˜
1332, 1436, 1699, 1749 cm–1. MH+ 238.1 calcd. 238.1. C11H11NO5
(237.21): found: C 55.70, H 4.67, N 5.90; calcd.: C 55.70, H 4.65,
N 5.68.
General Procedure A, for Preparation of Dimethyl 4-Alkylpyridine-
2,6-dicarboxylates 8a and 8d: Aqueous solutions of FeSO4
(1 mmol) and H2O2 (30% aqueous solution, 5 mmol) were added
dropwise over 15 min at 0 °C with vigorous stirring to a mixture of
dimethyl pyridine-2,6-dicarboxylate (0.49 g, 2.5 mmol), an alde-
hyde (7.5 mmol), and H2SO4 (30% aqueous solution, 15 mL). The
reaction mixture was stirred for 15 min at 0 °C, treated with satu-
rated aq. K2CO3 to pH 2, and extracted with ethyl acetate. Com-
bined extracts were dried and evaporated, and the residue was puri-
fied by flash chromatography to give compounds 8a and 8d.
Dimethyl 4-Benzoylpyridine-2,6-dicarboxylate (7c): This compound
was prepared from dimethyl pyridine-2,6-dicarboxylate (4.88 g)
and benzaldehyde (5.3 g). Chromatography with toluene/ethyl ace-
tate 3:1 provided title compound (2.18 g, 29%) along with reco-
1
vered dimethyl pyridine-2,6-dicarboxylate (1.46 g, 30%). H NMR
(300 MHz, CDCl3): δ = 4.02 (s, 6 H), 7.52 (t, J = 7.6 Hz, 2 H),
7.66 (t, J = 7.3 Hz, 1 H), 7.78 (d, J = 7.3 Hz, 2 H), 8.52 ppm (s, 2
H). 13C NMR (75 MHz): δ = 53.3, 127.0, 128.9, 130.0, 134.9, 147.2,
Dimethyl 4-Ethylpyridine-2,6-dicarboxylate (8a): This compound
was prepared from dimethyl pyridine-2,6-dicarboxylate (0.49 g)
and propionic aldehyde (0.44 g) Chromatography with hexane/ethyl
148.9, 164.4, 193.1 ppm. IR (film): ν = 700, 1255, 1279, 1440, 1669,
˜
1724 cm–1. MH+ 300.1 calcd. 300.1. C18H13NO5 (299.28): found: C
64.15, H 4.41, N 4.61; calcd.: C 64.21, H 4.35, N 4.68.
1
acetate (7:3 to 1:1) provided the title compound (0.32 g, 57%). H
NMR (200 MHz, CDCl3): δ = 1.29 (t, J = 7.5 Hz, 3H), 2.82 (q, J
= 7.5 Hz, 2 H), 4.02 (s, 6 H), 8.16 ppm (s, 2 H). 13C NMR
(75 MHz): δ = 13.8, 27.9, 52.9, 127.5, 147.9, 155.9, 165.1 ppm. IR
Dimethyl 4-(Hydroxymethyl)pyridine-2,6-dicarboxylate (9): Aque-
ous solutions of FeSO4·7H2O (14.4 g, 52 mmol) and H2O2 (30%
solution, 40 mL, 0.35 mol) were added dropwise over 1 h to a mix-
ture of dimethyl pyridine-2,6-dicarboxylate (10.2 g, 52 mmol),
methanol (30 mL), and H2SO4 (30% aqueous solution, 70 mL).
The reaction mixture was stirred for an additional 15 min, treated
with saturated aq. K2CO3 to pH 2, and extracted with ethyl acetate.
The combined extracts were dried and evaporated, and the residue
was separated by flash chromatography to yield a mixture of the
title compound 9 and unreacted dimethyl pyridine-2,6-dicarboxyl-
(film): ν = 646, 908, 1217, 1253, 1363, 1444, 1728 cm–1. MH+ 224.1
˜
calcd. 224.1. C11H13NO4 (223.23): found: C 58.96, H 5.87, N 6.44;
calcd. C 59.18, H 5.83, N 6.30.
Dimethyl 4-Isopropylpyridine-2,6-dicarboxylate (8d): This com-
pound was prepared from dimethyl pyridine-2,6-dicarboxylate
(0.49 g) and isobutyric aldehyde (0.54 g) Chromatography with hex-
ane/ethyl acetate (7:3 to 1:1) provided the title compound (0.40 g,
1
76%). H NMR (300 MHz, CDCl3): δ = 1.33 (d, J = 6.9 Hz, 6 H), ate.
1400
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Free-Radical Approach to 4-Substituted Dipicolinates
FULL PAPER
[5] B. Schmidt, D. K. Ehlert, Tetrahedron Lett. 1998, 39, 3999–
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[9] Chelidamic acids can, however, be synthesized from acetone
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[10] H. Nishiyama, S. Yamaguchi, M. Kondo, K. Itoh, J. Org.
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For large scales the resultant mixture was separated by the follow-
ing procedure. Chlorotrimethylsilane (9.0 mL, 71 mmol) and hexa-
methyldisilazane (15 mL, 71 mmol) were added to a solution of the
reaction mixture in CH2Cl2 (120 mL). The reaction mixture was
stirred for 70 min at room temperature, the precipitate of starting
dimethyl pyridine-2,6-dicarboxylate was filtered off, and the filtrate
was evaporated. The residue was diluted in 40 mL of a 2:1 mixture
of ether and petroleum ether and washed with water. The aqueous
solution was extracted with diethyl ether, the combined organic
solutions were evaporated, and the residue was dissolved in a mix-
ture of MeOH (10 mL) and aqueous HCl (10%, 10 mL). After 16 h
the resultant residue of title compound 9 was filtered (2.85 g, 24%).
1H NMR (300 MHz, CDCl3, after exchange of OH proton with
D2O): δ = 4.02 (s, 6 H), 4.89 (d, J = 5.4 Hz, 2 H), 8.31 ppm (s, 2
H). 13C NMR (75 MHz): δ = 53.2, 62.8, 125.3, 148.2, 153.5,
165.1 ppm. IR (film): ν = 784, 909, 1227, 1369, 1452, 1699, 1722,
˜
3486 cm–1. MH+ 226.1 calcd. 226.1. C10H11NO5 (225.20): found: C
53.08, H 5.19, N 6.05; calcd.: C 53.33, H 4.89, N 6.22. Chromato-
graphic separation with hexane/ethyl acetate (7:3 to 1:2) in an iden-
tical experiment provided a 30% yield of the title compound and
38% recovery of starting material.
Dimethyl 4-(2-Hydroxyethyl)pyridine-2,6-dicarboxylate (11): Solu-
tions of FeSO4·7H2O (4.17 g, 15 mmol) and H2O2 (30% aqueous
solution, 12 mL, 105 mmol) were added dropwise to a mixture of
dimethyl pyridine-2,6-dicarboxylate (2.93 g, 15 mmol), propane-
1,3-diol (13 mL, 180 mmol), and H2SO4 (30% aqueous solution,
20 mL). The reaction mixture was stirred for 15 min after comple-
tion of the addition, treated with saturated aq. K2CO3 to pH 2,
and extracted with ethyl acetate. The combined extracts were dried
and evaporated, and the residue was purified by flash chromatog-
raphy (hexane/ethyl acetate, 7:3 to 1:2) to yield the title compound
1
11 (1.29 g, 32%) and recovered starting material (25%). H NMR
(300 MHz, CDCl3): δ = 3.02 (t, J = 6.2 Hz, 2 H), 4.00 (t, J =
6.2 Hz, 2 H), 4.04 (s, 6 H), 8.23 ppm (s, 2 H). 13C NMR (75 MHz):
δ = 38.0, 53.0, 61.6, 128.7, 147.8, 151.6, 165.1 ppm. IR (film): 734,
909, 1218, 1253, 1363, 1445, 1604, 1729, 2955, 3450 cm–1 (br). MH+
(electrospray in the presence of MeSO3H): 240.3. C11H13NO5
(239.22): found: C 55.25, H 5.48, N 5.80; calcd.: C 55.23, H 5.48,
N 5.86.
[22] To the best of our knowledge, there are no quantitative data
on the basicity of dipicolinates in water media. Several mea-
surements[4] were done in dichloromethane, while attempts to
perform the measurements in methanol solutions failed.
[23] Substitutions in 4-cyanopyridine was reported to produce vari-
able amounts of 3-substitution: F. Coppa, F. Fontana, E. Laz-
zarini, F. Minisci, G. Pianese, L. Zhao, Tetrahedron Lett. 1992,
33, 3057–3060.
Acknowledgments
This research was supported by the Israel Science Foundation
(Grant No. 176/02-1).
[1] M. Latva, H. Takalo, K. Simberg, J. Kankare, J. Chem. Soc.,
Perkin Trans. 2 1995, 995–999; b) J. B. Lamture, B. Iverson,
M. E. Hogan, Tetrahedron Lett. 1996, 37, 6483–6486.
[24] G. P. Gardini, F. Minisci, J. Chem. Soc. 1970, 929–929.
[2] a) W. Berson, J. D. Auslander, Patent US5542971, 1996-08-06; [25] C. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu, Chem. Rev.
b) J. Guilford, D. Yan, Patent US6402986, 2002-06-11; c) R. L.
Hale, D. W. Solas, Patent WO8904826, 1989-06-01.
[3] For a recent review on pybox ligands, see: G. Desimoni, G.
Faita, P. Quadrelli, Chem. Rev. 2003, 103, 3119–3154.
[4] a) O. Storm, U. Lüning, Eur. J. Org. Chem. 2002, 3680–3685;
b) O. Storm, U. Lüning, Eur. J. Org. Chem. 2003, 3109–3116.
1999, 99, 1991–2070, see pages 1999–2000 for decarbonylation
rates.
[26] Yields in procedure B are recovery-based.
[27] Formation of dimerization product of α-hydroxybenzyl-type
radicals has been reported.[21]
Received: September 7, 2004
Eur. J. Org. Chem. 2005, 1397–1401
www.eurjoc.org
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