Some derivatives of 5-hydroxy-2-pyridone(2,5-dihydroxypyridine)

Article abstract of DOI:10.3184/174751914X13896383516701

The syntheses of 5-hydroxy-6-bromo-2-pyridone, 5-hydroxy-6-nitroso-2- pyridone, 3-bromo-5-acetoxy-2-pyridone, and 3-nitro-5-acetoxy-2-pyridone are described.

Full text of DOI:10.3184/174751914X13896383516701

JOURNAL OF CHEMICAL RESEARCH 2014
FEBRUARY, 121–122
RESEARCH PAPER 121
Some derivatives of 5‑hydroxy‑2‑pyridone(2,5‑dihydroxypyridine)
Edward J. Behrman
Department of Chemistry and Biochemistry, The Ohio State University, 484 W. 12th Avenue, Columbus, Ohio 43210, USA
The syntheses of 5‑hydroxy‑6‑bromo‑2‑pyridone, 5‑hydroxy‑6‑nitroso‑2‑pyridone, 3‑bromo‑5‑acetoxy‑2‑pyridone, and
3‑nitro‑5‑acetoxy‑2‑pyridone are described.
Keywords: Elbs oxidation, nitration, nitrosation, bromination, 5‑hydroxy‑2‑pyridone
by direct nitrosation.10,11 We provide a fuller characterisation
Results and discussion
but attempts to oxidise the product to the nitro derivative with
6‑Chloro‑ and 6‑methyl‑5‑hydroxy‑2‑pyridone form crystals
which contain channels capable of trapping solvent molecules.1,2
This finding stimulated a search for other channel‑forming
structures. This has not been successful2 but it has led to the
synthesis of a number of derivatives of 5‑hydroxy‑2‑pyridone.
Members of this class of molecules are very potent radical‑
trapping anti‑oxidants.3
2,6‑Dibromo‑ and 2,6‑difluoropyridine are commercial
productswhichareeasilytransformedtothemonohalopyridones
in alkali.4,5 Treatment of these monohalo‑2‑pyridones with
peroxydisulfate (Elbs oxidation)6 should then give rise to the
sulfate esters of new 6‑substituted 5‑hydroxy‑2‑pyridones.
The 6‑bromo derivative of 5‑hydroxy‑2‑pyridone (1) was
easily made. This synthesis has been described briefly in
the Supplementary Materials to ref. 2. We were, however,
unsuccessful in isolating the product of an Elbs oxidation on
6‑fluoro‑2‑pyridone and in the case of the iodo analogue, we
could not convert it to 6‑iodo‑2‑pyridone.
We then explored a different route to these 6‑substituted
derivatives involving the reaction of various electrophiles
with 5‑hydroxy‑2‑pyridone and some of its derivatives. Two
difficulties were encountered: formation of the azaquinone
dimer and substitution at the 3‑position.
The 6‑nitro derivative was reported to be formed by
treatment of 5‑hydroxy‑2‑pyridone with dilute nitric acid7 but
this procedure failed in our hands. Instead, a variety of standard
nitration, as well as iodination, and bromination procedures
produced the azaquinone dimer due to the easy oxidation of the
substrate7–9 with coupling at the 3‑position (2). Nitrosation at
the 6‑position using nitric acid in acetic acid gave the 6‑nitroso
compound, due to reduction of the nitric acid by the substrate,
in small yield. The 6‑nitroso compound is more easily prepared
hydrogen peroxide or dimethyldioxirane did not succeed. We
therefore turned to modification of the 5‑hydroxyl group.
5‑Acetoxy‑2‑pyridone12 was converted to the 3‑bromo (3) and
3‑nitro (4) derivatives by reaction with nitric acid or bromine
(Scheme 1). Under the same conditions, 2‑pyridone‑5‑sulfate7
gave 3‑bromo‑2‑pyridone‑5‑sulfate. This was identified in a
mixture with the starting material by observation of its meta‑
coupled protons at δ 7.80 (d, H‑4, J=2.7 Hz) and 7.25 (d, H‑6,
J=2.7 Hz). Attempts to nitrosate 5‑acetoxy‑2‑pyridone were
unsuccessful.
Experimental
2,6‑Dichloro‑, 2,6‑dibromo‑, and 2,6‑difluoropyridine were products
from Alfa‑Aesar. 5‑Hydroxy‑2‑pyridone, 2‑pyridone‑5‑sulfate, and
5‑acetoxy‑2‑pyridone were made by published methods6,7,12. NMR
spectra were taken on a Bruker instrument at 600 MHz in DMSO‑d6
with TMS as reference unless otherwise specified. IR spectra were
recorded as Nujol mulls on a Nicolet model 410.
5-Hydroxy-6-bromo-2-pyridone (1) [with N. Eikhoff]: 6‑Bromo‑2‑
pyridone was synthesised by the method of Newkome et al.4, m.p. 125–
126 °C (lit. 123–124°C). UV(95% ethanol) λmax 279 nm, 5650 M–1 cm–1,
222 nm. IR 1657, 1611, 1579, 1479, 1352, 1245, 1158, 1130, 997, 893,
835, 783, 725, 675. 1H NMR δ 7.55 (dd, H‑4, J=7.8 Hz), δ7.03 (d, H‑5,
J=7.5 Hz), δ 6.63 (d, H‑3, J=8.1 Hz). pKa (50% ethanol) 8.14±0.1
(compare 6‑H, 11.6, and 6‑Cl, 7.8). The Elbs oxidation of 6‑bromo‑
2‑pyridone was carried out on a 0.01 mol scale by the general method
previously described6 using KOH and K2S2O8. The reaction mixture
was neutralised with conc. H2SO4 and then dried. The salt cake was
extracted with isopropanol to remove unreacted starting material
(40–60%). The extracted material was treated with 2:1 acetone‑
water according to Smith13 to dissolve the sulfate esters and filtered.
The filtrate, containing both 6‑bromo‑2‑pyridone‑5‑sulfate and
1
3
2
4
Scheme 1
* Correspondent. E‑mail: Behrman.1@osu.edu
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122 JOURNAL OF CHEMICAL RESEARCH 2014
the 3‑sulfate isomer, was dried. Treatment of 0.7 g of this material
with 10 mL of 48% HBr at RT gave a precipitate containing only the
p‑isomer. The ester was collected by filtration and upon standing
at room temperature, the damp material underwent hydrolysis to
the title compound as the hydrobromide. (The bromo group is rather
easily displaced so that hydrolysis under the usual conditions yields
mostly 2,3,6‑trihydroxypyridine.) The ML deposited crystals of
the hydrobromide upon standing at 5 °C. After drying, sublimation
was carried out at 0.5 mm Hg at about 175°C to give the product as
the hydrobromide in an amorphous state. The hydrobromide was
converted to the free base by dissolution in methanol and the addition
of an equivalent of ammonium formate and a few drops of 88% formic
acid. Sublimation at 100–110 °C gave the free base contaminated with a
little ammonium formate. Crystallisation from dichloroethane (25 mg
from 5 mL) gave pure material. Anal. calcd for C5H4NO2Br: Br, 42.05;
found: Br, 42.06%. M.p. 154–155 °C (dec.). UV(water): λmax 304 nm,
4700 M–1 cm–1, sh. 334, 225 nm. Ferric chloride colour pink, λmax
509 nm (sh 544 nm). IR 1660, 1605, 1530, 1456, 1401, 1288, 1267, 1246,
1051, 925, 815 cm–1. 1H NMR δ 10.58 (s, NH), 9.94(s, OH), 7.22 (d, H‑4,
J=8.5 Hz), 6.50 (d, H‑3, J=8.5 Hz). With drier solvent, NH coupling
was observed: δ 7.09(t, J=51 Hz).
5-Hydroxy-6-nitroso-2-pyridone: 5‑Hydroxy‑2‑pyridone (0.280 g,
2.5 mmol) was dissolved in 4 mL 6M HCl. The solution was cooled
and then 3 mL of a solution of NaNO2 (0.31 g, 4.5 mmol) in cold water
was added dropwise and with stirring. A precipitate formed almost
immediately. After 30 min, the product was filtered, washed with cold
water, and air‑dried. Yield 0.280 g or 70%. IR 1702, 1660, 1589, 1504,
1420, 1355, 1338, 996, 870, 822, 789, 766, 563 cm–1. NMR (600 MHz,
CD3OD): δ 6.96 (d, H‑3, J=10.3 Hz), δ 6.93(d, H‑4, J=10.3 Hz). In
DMSO‑d6, the downfield doublet was split in addition by the NH
proton with a 2 Hz coupling. The UV spectrum matches the data of
ref. 11.
allowed to stand at room temperature for 30 min. Rotary evaporation
gave 0.4 g of a solid. Trituration with water (10 mL) and filtration gave
80 mg of pale pink needles, m.p. 183–184°C. IR(Nujol): 3052, 1762,
1
1667, 1634, 1198, 920, 908, 884, 856 cm–1. H NMR: δ 12.15(s, NH),
7.95 (d, H‑4, J=2.8 Hz), 7.48 (d, H‑6, J=2.6 Hz), 2.21 (s, Me). Anal.
calcd for C7H6NO3Br: C, 36.22; H, 2.61; N, 6.04; found: C, 36.00; H,
2.41; N, 6.01%.
3-Nitro-5-acetoxy-2-pyridone (4): 5‑Acetoxy‑2‑pyridone (153 mg,
1 mmol) was dissolved in 1 mL acetic acid, 0.075 mL 70% nitric acid
(1.17 mmol) was added and the mixture allowed to stand overnight at
room temperature. Little reaction was observed so the mixture was
heated in a boiling water bath for 15 min. Upon cooling, a precipitate
formed. This was filtered, washed with cold acetic acid and then water
to yield 40 mg of pale yellow needles, m.p. 246–247°C. IR: 3076,
1765, 1756, 1709, 1663, 1602, 1548, 1338, 1301, 1211, 1052, 864, 804,
777 cm–1. 1H NMR δ 12.98(s, NH), 8.46(d, H‑4, J=3.0 Hz), 7.96 (d, H‑6,
J=2.9 Hz), 2.24 (s, Me). Anal. calcd for C7H6N2O5: C, 42.42; H, 3.05; N,
14.14; found: C, 42.61; H, 2.63; N, 13.76%.
Received 13 December 2013; accepted 31 December 2013
Paper 1302342 doi: 10.3184/174751914X13896383516701
Published online: 5 February 2014
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