Convenient multigram synthesis of 4-chloropyridine-2,6-dicarbonyl dichloride

Article abstract of DOI:10.1055/s-0028-1083348

A method amenable to the multigram-scale preparation of 4-chloropyridine-2,6-dicarbonyl dichloride is described. The key transformation is the deoxygenative chlorination of the pyridine N- oxide with oxalyl choride. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083348

SHORT PAPER
713
Convenient Multigram Synthesis of 4-Chloropyridine-2,6-dicarbonyl
Dichloride
Kazuhiko Mitsui, Jon R. Parquette*
Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA
Fax +1(614)2921685; E-mail: parquett@chemistry.ohio-state.edu
Received 12 September 2008
Cl
Abstract: A method amenable to the multigram-scale preparation
of 4-chloropyridine-2,6-dicarbonyl dichloride is described. The key
transformation is the deoxygenative chlorination of the pyridine N-
oxide with oxalyl choride.
(COCl)2, DMF (cat.)
CH2Cl2
O
O
+
O
O
N
–10 °C to r.t., 72 h
99%
N
O
O
O
–
Cl
Cl
H
H
Key words: 4-chloropyridine-2,6-dicarbonyl dichloride, supramo-
lecular chemistry, deoxygenative chlorination, carboxylic acid
chlorides, nitrogen heterocycles
2
3
Scheme 2
The unique efficacy of oxalyl chloride–N,N-dimethyl-
formamide at –10 °C in producing 3 is noteworthy. For
example, the reaction fails in the absence of catalytic N,N-
dimethylformamide. Significant amounts of methyl 3-
chloropyridine-2,6-dicarboxylate were obtained after
quenching with methanol, when the reaction was carried
out with oxalyl chloride–N,N-dimethylformamide at am-
bient temperature or when thionyl chloride–N,N-dimeth-
ylformamide was employed. Similarly, treatment of 2
with phosphorus pentachloride or phosphorus trichloride,
followed by methanol, afforded methyl pyridine-2,6-di-
carboxylate as a byproduct in 26% and 100% yields, re-
spectively.
4-Chloropyridine-2,6-dicarbonyl dichloride (3) serves as
a versatile building block in organometallic,1 supramolec-
ular,2 bioorganic,3 and dendrimer chemistry.4 The synthe-
sis of 3 generally proceeds via chelidamic acid, which is
prepared using a lengthy multistep protocol from diethyl
oxalate and acetone.5 Although chelidamic acid monohy-
drate is commercially available, we were interested in a
more efficient and economical approach to the large-scale
preparation of 3. Herein, we report an expedient and scal-
able, two-step preparation of 3 from inexpensive pyridine-
2,6-dicarboxylic acid (1).
We hypothesized that a selective chlorination at the 4-po-
sition of 1 could be accomplished by deoxygenative halo-
genation of the corresponding N-oxide.6 Accordingly, 2
was prepared in 56% yield on a 100-gram scale by sodium
tungstate catalyzed oxidation of 1 with 30% aqueous hy-
drogen peroxide (Scheme 1).7
In summary, we have developed a convenient method for
the large-scale preparation of 4-chloropyridine-2,6-dicar-
bonyl dichloride. The present strategy provides multigram
quantities of 3 in two steps from an inexpensive starting
compound, and circumvents the need to prepare che-
lidamic acid.
30% aq H2O2
Na2WO2⋅2H2O (0.6 mol%)
O
O
O
O
+
N
N
Melting points were determined in open capillaries and are uncor-
rected. 1H NMR spectra were recorded at 400 MHz and 13C NMR
spectra at 100 MHz on a Bruker DPX-400 instrument. All reactions
were performed in oven- or flame-dried glassware under a nitrogen
atmosphere unless otherwise noted. DMF was dried by distillation
from activated 4 Å molecular sieves and CH2Cl2 was distilled from
CaH2.
O
O
100 °C, 16 h
56%
O
O
O
–
H
H
H
H
1
2
Scheme 1
Exposure of 2,6-dicarboxypyridine 1-oxide (2) to oxalyl
chloride in the presence of catalytic N,N-dimethylform-
amide at –10 °C provided 3 in 99% yield on a 50-gram
scale. (Scheme 2). Examination of the crude by 1H NMR
spectroscopy and melting point analysis demonstrated
that the material was essentially pure in crude form. How-
ever, further purification could be achieved by sublima-
tion at 110 °C (0.1 Torr)8 if necessary.
2,6-Dicarboxypyridine 1-Oxide (2)7
Na2WO2·2H2O (6.5 g, 3.3 mmol) was added to a suspension of 1
(100 g, 598 mmol) in 30% aq H2O2 (300 mL). The mixture was
heated to 100 °C and stirred for 2 h. An additional amount of 30%
aq H2O2 (720 mL) was added at r.t. The mixture was stirred at 100
°C for 14 h, during which time the cloudy white reaction mixture
became homogeneous. The mixture was cooled to 0 °C and a white
precipitate was separated by filtration, then washed with ice-cold
H2O (2 × 60 mL). An additional amount of product was extracted
from the aqueous filtrate with CHCl3 (3 × 600 mL). The combined
white solid crude material was recrystallized from H2O (300 mL).
The isolated product was then dried with P2O5 under reduced pres-
SYNTHESIS 2009, No. 5, pp 0713–0714
x
x
.
x
x
.2
0
0
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Advanced online publication: 02.02.2009
DOI: 10.1055/s-0028-1083348; Art ID: M05408SS
© Georg Thieme Verlag Stuttgart · New York

714
K. Mitsui, J. R. Parquette
SHORT PAPER
sure (5 Torr) while heating in an oil bath (80 °C) for 15 h; this gave
pure 2,6-dicarboxypyridine 1-oxide (2).
Yield: 61.7 g (56%); white solid; mp 158–161 °C (H2O) (Lit.7a 155–
157 °C).
1H NMR (400 MHz, DMSO-d6): d = 7.95 (t, J = 8.0 Hz, 1 H), 8.23
(d, J = 7.8 Hz, 2 H), 15.9 (br s, 2 H).
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13C NMR (100 MHz, DMSO-d6): d = 129.4, 132.7, 139.7, 161.3.
4-Chloropyridine-2,6-dicarbonyl Dichloride (3)
Oxalyl chloride (234 mL, 2.73 mol, 10 equiv) was added slowly
over 5 min under an atmosphere of N2 to a suspension of 2 (50 g,
273 mmol) in anhyd CH2Cl2 (546 mL) at –10 °C in a salt/ice bath.
After the mixture had stirred for 10 min, one drop (ca. 10 mL) of an-
hyd DMF was added to the suspension. The resulting mixture was
warmed to r.t. gradually over 12 h, then stirred at r.t. for an addition-
al 60 h. The excess oxalyl chloride, solvent, and volatiles were re-
moved under reduced pressure to afford crude 3.
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Yield: 64.6 g (99%); white crystalline solid with a faint yellow
color; mp 95–97 °C (CH2Cl2) (Lit.9 97–98 ºC).
1H NMR (400 MHz, CDCl3): d = 8.32 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 128.9, 147.9, 150.2, 168.6.
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Acknowledgment
This work was supported by the National Science Foundation
(CHE-0750004).
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Synthesis 2009, No. 5, 713–714 © Thieme Stuttgart · New York