Y. M. Ma, R. C. Hider / Tetrahedron Letters 51 (2010) 5230–5233
5233
base LTMP as the metalation reagent. To obtain compound 24, the
Acknowledgement
5-hydroxy group of 21 required protection, which was followed by
lithiation at C6 with LTMP for 20 h and methylation and hydroge-
nation. In contrast to the 2-fluoropyridine derivatives, when the 3-
fluoropyridine analogue 24 was treated with methyl iodide over-
night, TLC showed that the starting material was consumed and
a single product was detected. NMR and MS demonstrated that
the expected product, the 1-methylpyridinium derivative, was
not formed, but instead the 1-methylpyridin-4-one derivative 25
was obtained. To the best of our knowledge, this type of reaction
has not been previously reported to occur under such mild condi-
tions. A possible mechanism for this rearrangement is outlined in
Scheme 3. Although fluorine at C2 inactivates the lone pair of elec-
trons on N1 and prevents reaction with methyl iodide, fluorine at
C3 apparently has less of an effect on the reactivity of N1. However,
the resulting intermediate 1-methylpyridinium iodide salt is
unstable due to the inductive effect of the fluorine at C3, which
simultaneously converts into the more stable 1-methylpyridin-4-
one analogue and releases methyl iodide. In fact, when an excess
of ethyl iodide was used instead of methyl iodide, a mixture of
1-ethyl- and 1-methyl-pyridin-4-ones was produced. Thus in order
to obtain a clean quantitative 1-alkylpyridin-4-one, the same alkyl
group must be used to protect the 4-hydroxy group as is demon-
strated with the preparation of 4m. Intermediate 27 can be pro-
duced from 21 by either protection of the 5-hydroxy group
followed by reduction to remove the 2-chlorine or a reverse proce-
dure via 28. When 27 was lithiated with LDA, C2 had priority over
C6 to be deprotonated, and upon methylation gave 26. Intermedi-
ate 28 (where PG = methyl) can also be obtained from 4-chloro-3-
fluoropyridine (30) via alkoxylation at C4 followed by the introduc-
tion of a hydroxy group at C5. However, when the 4-OH group was
ethyl-protected (29, PG = ethyl), a clean 2-hydroxy analogue was
produced under the same conditions. In similar fashion to 24, com-
pound 28, when reacted with methyl or ethyl iodide, resulted in
the formation of 4l and 4m, respectively, in quantitative yields.
The 5- and 4-alkyl protecting groups of 24–28 were removed by
reacting with BBr3 to produce 4h–k, respectively.19
In conclusion, several 2- or 5-fluoro-containing 3-hydroxypyri-
din-4-ones have been synthesised where one or more methyl or
ethyl groups were also introduced to modulate the lipophilicity
for improved membrane permeability. Overall, the choice of a spe-
cific lithiating reagent is the key factor for the site specific proton–
lithium exchange. Generally, metalation occurs at the ortho posi-
tion of an electronegative element except for reactions with USB,
which prefers to attack the 6-position. When two different types
of electronegative atom are present at adjacent vacant positions,
metalation predominates at the more electronegative site (see
the conversion from 27 into 26). Contrary to 2-fluoro 4-alkoxypyri-
dines, the 3-fluoro analogues behave in a different way, where not
only the alkyl group is attached to N1, but also the 4-hydroxy al-
kyl-protecting group is removed simultaneously when reacted
with an alkyl iodide. Metabolic studies are currently in progress
and we believe that several of the fluoro analogues described in
this work will have advantages over deferiprone.
The financial support from British Technology Group (BTG) is
gratefully acknowledged.
References and notes
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2002, 67, 4487–4493.
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2002, 67, 3272–3276.
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18. General procedure for introduction of a hydroxy group on the pyridine ring: A
solution of fluorine-substituted pyridine derivative (10 mmol) in anhydrous
THF (20 ml) under N2 was cooled to À78 °C in a dry ice/acetone bath. To this
solution was added a solution of a lithium base as indicated in Schemes 1 and 2
(11 mmol), slowly. The mixture was stirred at À78 °C for the amount of time
indicated. To the mixture was added trimethoxyborane (2.4 ml) and the
reaction mixture was stirred for 2 h, followed by addition of peracetic acid
(3.6 ml; 32% in dilute AcOH). The mixture was allowed to warm to 0 °C with
stirring for 1 h. Next, the mixture was cooled to À20 °C, and sodium dithionite
(4 g in 10 ml of H2O) was added slowly. The mixture was extracted with EtOAc
(80 ml) or CH2Cl2 (80 ml) and the extract dried and concentrated. The residue
was purified by chromatography to give the desired products.
19. Selected NMR and MS data: 2-Fluoro-3-hydroxy-6-methyl-1H-pyridin-4-one
(4d): 1H NMR (400 MHz, DMSO-d6) d: 6.61 (s, 1H, C5-H), 5.99 (br s), 2.21 (s, 3H,
Me). 19F NMR (376 MHz, DMSO-d6) d: À90.71 (s). 13C NMR (100 MHz, DMSO-
d6) d: 22.23 (s, Me), 109.50 (d, J = 3 Hz, C5–H), 125.04 (d, J = 29 Hz, C3), 144.52
(d, J = 13 Hz, C6), 152.92 (d, J = 227 Hz, C2), 156.26 (d, J = 8 Hz, C4). HRMS:
Calcd for C6H7NO2F (M+1)+, 144.0461. Found, 144.0463. 2-Fluoro-3-hydroxy-5-
methyl-1H-pyridin-4-one (4f): 1H NMR (400 MHz, DMSO-d6) d: 7.59 (br s), 7.36
(s, 1H, C6-H), 2.07 (s, 3H, Me). 19F NMR (376 MHz, DMSO-d6) d: À91.60 (s). 13
C
NMR (100 MHz, DMSO-d6) d: 12.53 (s, Me), 119.84 (d, J = 3 Hz, C5), 126.56 (d,
J = 29 Hz, C3), 135.54 (d, J = 16 Hz, C6–H), 152.69 (d, J = 224 Hz, C2), 154.12 (d,
J = 8 Hz, C4). HRMS: Calcd for C6H7NO2F (M+1)+, 144.0461. Found, 144.0478. 5-
Fluoro-3-hydroxy-2-methyl-1H-pyridin-4-one (4h): 1H NMR (400 MHz, DMSO-
d6) d: 8.55 (d, J = 5.0 Hz, 1H, C6–H), 4.54 (br s), 2.54 (s, 3H, Me). 19F NMR
(376 MHz, DMSO-d6) d: À148.82 (s). 13C NMR (100 MHz, DMSO-d6) d: 14.04 (s,
Me), 121.88 (d, J = 32 Hz, C6–H), 137.31 (s, C2), 144.11 (d, J = 7 Hz, C3), 148.73
(d, J = 238 Hz, C5), 150.48 (d, J = 12 Hz, C4). HRMS: Calcd for C6H7NO2F (M+1)+,
144.0461. Found, 144.0468. 3-Fluoro-5-hydroxy-2-methyl-1H-pyridin-4-one
(4j): 1H NMR (400 MHz, DMSO-d6) d: 8.04 (d, J = 0.5 Hz, 1H, C6–H), 4.30 (br
s), 2.64 (d, J = 2.8 Hz, 3H, Me). 19F NMR (376 MHz, DMSO-d6) d: À146.32 (s). 13
C
NMR (100 MHz, DMSO-d6) d: 12.67 (s, Me), 123.02 (s, C6–H), 134.77 (d,
J = 27 Hz, C2), 145.25 (d, J = 7 Hz, C5), 147.32 (d, J = 238 Hz, C3), 150.60 (d,
J = 11 Hz, C4). HRMS: Calcd for C6H7NO2F (M+1)+, 144.0461. Found, 144.0468.