Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning

Article abstract of DOI:10.1016/j.jfluchem.2011.05.028

Fluoroheterocyclic aldoximes were screened as therapeutic agents for the treatment of anticholinesterase poisoning. 2-Fluoropyridine-3- and -6-aldoxime, and 3-fluoropyridine-2- and -4-aldoxime, were synthesised. Attempts to obtain 3,5,6-trifluoropyridine-2,4-bis(aldoxime) and -2-aldoxime, however, proved unsuccessful. Pentafluorobenzaldoxime was prepared by oximation of pentafluorobenzaldehyde. Acid dissociation constants (pK_a) and second-order rate constants (k_ox-) of the fluorinated pyridinealdoximes towards sarin were measured. 2,3,5,6-Tetrafluoropyridine-4- aldoxime had the best profile: its k_ox- approached that of the therapeutic oxime P2S (310 vs. 120 l mol^-1 min^-1), but its higher pK_a (9.1 vs. 7.8) fell short of the target figure of 8 required for reactivation of inhibited acetylcholinesterase in vivo. N-alkylation of the fluorinated pyridine-aldoximes may reduce their pK _a nearer to 8 and enhance their therapeutic potential. Crown Copyright

Full text of DOI:10.1016/j.jfluchem.2011.05.028

Journal of Fluorine Chemistry 132 (2011) 541–547
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of some fluorine-containing pyridinealdoximes of potential use
for the treatment of organophosphorus nerve-agent poisoning
Christopher M. Timperley a, , R. Eric Banks b,1, Ian M. Young b,1, Robert N. Haszeldine b,1
*
a Detection Department, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK
b Chemistry Department, The University of Manchester Institute of Science and Technology (UMIST), Manchester M60 1QD, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
Fluoroheterocyclic aldoximes were screened as therapeutic agents for the treatment of anticholinester-
ase poisoning. 2-Fluoropyridine-3- and -6-aldoxime, and 3-fluoropyridine-2- and -4-aldoxime, were
synthesised. Attempts to obtain 3,5,6-trifluoropyridine-2,4-bis(aldoxime) and -2-aldoxime, however,
proved unsuccessful. Pentafluorobenzaldoxime was prepared by oximation of pentafluorobenzalde-
hyde. Acid dissociation constants (pKa) and second-order rate constants (koxꢀ) of the fluorinated
pyridinealdoximes towards sarin were measured. 2,3,5,6-Tetrafluoropyridine-4-aldoxime had the best
profile: its koxꢀ approached that of the therapeutic oxime P2S (310 vs. 120 l molꢀ1 minꢀ1), but its higher
Received 31 January 2011
Received in revised form 5 May 2011
Accepted 29 May 2011
Available online 28 June 2011
Keywords:
Fluoropyridines
pKa (9.1 vs. 7.8) fell short of the target figure of
8 required for reactivation of inhibited
Fluorinated pyridinecarboxaldehydes
acetylcholinesterase in vivo. N-alkylation of the fluorinated pyridine-aldoximes may reduce their pKa
nearer to 8 and enhance their therapeutic potential.
Nerve agent
Oximes
2-PAM
Crown Copyright ß 2011 Published by Elsevier B.V. All rights reserved.
Sarin
1. Introduction
interested in the synthesis of AChE reactivators and their chemical
precursors.
Terrorist use of sarin in a Tokyo subway in 1995 highlighted the
threat from organophosphorus nerve agents (NAs) [1]. Despite an
effort spanning decades, treatment of NA poisoning is still
unsatisfactory and the search for improved antidotes continues
[2]. Some compounds with an N–OH group can reactivate
acetylcholinesterase (AChE) inhibited by NAs. An effective
reactivator is 1-methylpyridinium-2-aldoxime methanesulfonate
(P2S) which contains a pyridinium scaffold that binds reversibly to
the anionic site of inhibited AChE [3] and a nucleophilic oxime
group that ionises at physiological pH [4]. The resultant oximate
ion attacks and releases the NA residue, restoring normal enzyme
activity (Scheme 1) and nerve transmission.
Some bis-quaternary oximes such as obidoxime (Fig. 1) are
generally more effective against a broader range of NAs than
mono-quaternary oximes [5]. However none of the oximes
researched to date are sufficiently efficacious against all known
NAs. Finding an oxime sufficiently effective against AChE inhibited
by a variety of NAs is still an important task and many institutes are
Although a quaternary nitrogen atom is believed to be
necessary for binding the inhibited enzyme anionic site [5], it
limits passage of the compound through the blood-brain-barrier
(BBB) where uptake is thought desirable for combating the toxic
effects of NAs on the central nervous system [6,7]. The acid
dissociation constant (pKa) of the oxime group determines the
concentration of oximate ion and thus the rate of reactivation.
Studies by Porton scientists showed that under physiological
conditions (pH 7.4, 37 8C) only oximes with a pKa around 8 reacted
satisfactorily with organophosphorus compounds [8]. Oximes
having a pKa much less than 8 did ionise but the anion was too
feebly nucleophilic to enable reactivation to occur quickly. Those
having a pKa much greater than 8 did not ionise appreciably and
insufficient anion was available for reactivation. Adjusting the
charge on nitrogen, and hence binding to the anionic site and the
pKa, might be possible by adding fluorine atoms to the pyridine
scaffold. Exchange of H for F will increase size only slightly
˚
(respective van der Waals radii: 1.20 and 1.47 A) but will modulate
the charge on nitrogen and the lipophilicity [9], maybe enabling
the molecule to surmount the BBB.
This paper describes the synthesis of some fluorinated pyridine
aldoximes and an assessment of their potential for treating NA
poisoning. Synthetic work was conducted at the University of
Manchester Institute of Science and Technology (UMIST) during
* Corresponding author. Tel.: +44 1980 613566; fax: +44 1980 613371.
E-mail address: cmtimperley@dstl.gov.uk (C.M. Timperley).
1
Retired.
0022-1139/$ – see front matter. Crown Copyright ß 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.05.028

542
C.M. Timperley et al. / Journal of Fluorine Chemistry 132 (2011) 541–547
i-PrO
O
F
i-PrO
O
step 1
- HF
Acid dissociation constants and rates of reaction with sarin of
three of the fluorinated pyridinealdoximes were compared at
Porton with those obtained with P2S and some non-quaternized
analogues. These data have been mentioned briefly before [1], but
experimental details and a discussion of the results are now
presented for the first time.
HO-AChE
P
P
+
Me
Me O-AChE
HON=CH
N
step 2
+
Me
-
MeSO3
- HO-AChE
2. Results and discussion
P2S
2.1. Monofluorinated pyridinealdoximes
i-PrO
O
i-PrO
O
step 3
P
P
+
2.1.1.
a-Fluorinated pyridinealdoximes A and B
H2O
Me OH
NC
N
Me O N C
H
N
+
+
The Balz-Schiemann technique was used to convert 2-amino-3-
methylpyridine into 2-fluoro-3-methylpyridine (1) (Scheme 2),
permanganate oxidation of this to acid 2 followed by its conversion
to acyl chloride 3 was conducted according to literature instruc-
tions [14–17]. Rosenmund reduction was used to transform the
acyl chloride into carboxaldehyde 4. Previously this technique was
reported to give poor yields with heterocyclic acid chlorides [18],
yet homocyclic acid chlorides gave good yields if nuclear halogen
substituents were present. Our conversion of acid chloride 3 to
carboxaldehyde 4 in satisfactory yield (66%) demonstrated that
fluoroheterocyclic compounds could undergo facile catalytic
reduction by hydrogen in boiling xylene. Carboxaldehyde 4
reacted smoothly with hydroxylamine produced in situ from
hydroxylamine hydrochloride (15 min reflux in ethanolic NaOH
aq) to provide oxime A in 60% yield.
Me
Me
Scheme 1. Mechanism of AChE inhibition (step 1), reactivation by the therapeutic
oxime P2S (step 2), and formation of non-toxic products (step 3).
HON=HC
R
CH=NOH
R
N
N
+
+
-
O
2 Cl
R = H obidoxime (Toxogonin®) [5]
F
3,3'-difluoro-obidoxime [12]
2-Fluoropyridine-6-aldoxime (B) was prepared similarly from
2-amino-6-methylpyridine
39% ! -6-carboxylic acid 50% ! -6-carboxylic acid chloride
72% ! -6-carboxaldehyde 68% ! B 71%).
Fig. 1. Obidoxime and a difluorinated analogue.
(! 2-fluoro-6-methylpyridine
the period 1963–1966 [10] and compounds submitted to the then
Chemical Defence Experimental Establishment (CDEE) at Porton
Down (UK) for biological testing. Owing to British national security
restrictions at the time, which have now been lifted, neither the
synthetic work nor the screening results could be published; the
purpose of this paper is to remedy this situation. Note that the first
communications concerning fluorinated pyridinium aldoximes as
antidotes for nerve-agent poisoning appeared in the open literature
only recently (2009–2010) [11–13], derivatives of 3-fluoropyridine-
4-aldoxime (e.g. 3,30-difluoro-obidoxime, Fig. 1) being described. 3-
Fluoropyridine-4-aldoxime was one of the targets (A–I; Fig. 2)
involved in our researches initiated 48 years ago!
2.1.2.
b-Monofluorinated pyridinealdoximes C and D
Literature routes were adapted for transforming 2-amino-6-
methylpyridine into 3-fluoro-2-methylpyridine [19,20] (Scheme
3). Conversion of the
distillation [19]) to its 6-chloro analogue (7), followed by reductive
dechlorination then Balz–Schiemann fluorodediazoniation [20] of
the resulting aminopicoline 8, provided 3-fluoro-2-methylpyridine
(9). Condensation of 9 with benzaldehyde, as described for its non-
fluorinated analogue [21], followed by ozonolysis of the benzy-
lidine derivative 10 produced gave 3-fluoropyridine-2-carboxal-
dehyde (11) and hence access to oxime C.
b-nitro compound 5b (isolated by steam
The sequence used to obtain oxime C (Scheme 3) was applied to
2-amino-4-methylpyridine, the only difference being that the
products of nitration (3- and 5-isomers) were not separated but
jointly processed to provide 3-amino-4-methylpyridine 15 and
thence 3-fluoropyridine-4-aldoxime (D) (Scheme 4).
CH=NOH
F
F
N
F
N
CH=NOH
N
CH=NOH
A
B
C
CH=NOH
F
CH=NOH
F
Me
Me
Me
F
CO2H
F
aq KMnO4
reflux
NaNO2
F
F
F
F
F
40% aq HBF4
N
NH2
N
N
N
D
N
E
F
N
F
CH=NOH
1 41%
2 53%
SOCl2
CH=NOH
F
H
CH=NOH
F
CH=NOH
F
CHO
COCl
F
F
F
F
F
F
F
H2
H2NOH
EtOH
Pd-BaSO4
N
N
4
F
66%
N
3
F
42%
N
G
CH=NOH
N
H
CH=NOH
F
I
oxime A 60%
Fig. 2. UMIST-CDEE target oximes.
Scheme 2.

C.M. Timperley et al. / Journal of Fluorine Chemistry 132 (2011) 541–547
543
O2N
H2N
NO2
HNO3
+
H2SO4
H2N
N
Me
N
Me
H2N
N
Me
66%
5a
5b
NaNO2
HCl
NH2
NO2
Me
NO2
H2
Pd/C
POCl3
PCl5
N
8
Me
66%
Cl
N
HO
N
6
Me
7 95%
66%
EtONO
HBF4
F
F
F
i. O3
ii. H2
PhCHO
H
KOAc
Ac2O
I2 cat.
N
Me
N
N
CHO
H
Ph
36%
9
66%
10
11
47%
H2NOH
EtOH
F
N
CH=NOH
oxime C 37%
Scheme 3.
2.2. Polyfluorinated oximes
2.2.1. Pyridinealdoximes E-H
rather than undergoing ring substitution (at the time pentafluor-
obenzaldehyde 35 was more easily prepared than the related
mono- and polyfluorinated pyridine systems and therefore a good
test case). Oxime (I) was not screened for potential biological
activity because it lacked the nitrogen atom believed to be
necessary for AChE reactivation.
Tetrafluoropyridine-4-aldoxime (E) and 3,5,6-trifluoro-4-
methylpyridine-2-aldoxime (F) were reported long ago [22–24].
The favoured route (of three) to oxime (E) featured 4-position
propenylation of pentafluoropyridine (19) with MeCH55CHLi [22]
followed by ozonolysis of the product 20 and oximation of the
carboxaldehyde 24 produced (Scheme 5) [23,24]. In like manner
2,3,5,6-tetrafluoro-4-methylpyridine (27) was converted to 3,5,6-
trifluoro-4-methyl-2-propenylpyridine (28) and thence to 3,5,6-
trifluoro-4-methylpyridine-2-carboxaldehyde (29), the precursor
of oxime (F) (Scheme 6) [23].
Attempts to prepare formyl precursors of oximes G and H
started, respectively, from pentafluoropyridine and 2,3,5,6-tetra-
fluoropyridine (ex. C5F5N + LiAlH4 [22]). In both cases, propenyla-
tion featured as the chosen route to the aldehydes sought. Carried
out on a larger scale and giving a better product yield (85 vs. 62%)
than previously [22], this provided 3,5,6-trifluoro-2,4-dipropenyl-
pyridine (30), ozonisation of which followed by reduction, yielded
only an intractable tar (Scheme 7). Unchanged starting material
contaminated with traces of unidentified material and ‘tar’
resulted when 2,3,5,6-tetrafluoropyridine (32) was treated with
propenyl-lithium (Scheme 8).
2.3. Porton screening data
The classical approach adopted at Porton [26,27] for screening
potency of oximes as reactivators of inhibited AChE sought to
correlate a relevant thermodynamic property (e.g. pKa) with
nucleophilicity towards a particular NA (e.g. sarin). Nucleophilicity
towards the NA was assumed to reflect that towards inhibited
AChE. Acid dissociation constants for pyridinealdoximes and their
methiodides (2-, 3- and 4-PAM) [28–33] reflect the inductive and
conjugative effect of the nitrogen atom. Reactivating power of
inhibited enzyme decreases in the order 2-PAM (pKa 7.8) > 4-PAM
(8.5) ꢁ 3-PAM (9.2) [33,34].We measured pKa values and second-
order rate constants (koxꢀ) towards sarin of the fluorinated
pyridine aldoximes and some perprotio analogues (Table 1). A
fluorine atom in the 3-position barely affected the pKa of pyridine
2- and 4-aldoxime. The correlation that increased pKa increases
reactivity [26,27] was obeyed. The koxꢀ of 2,3,5,6-tetrafluoropyr-
idine-4-aldoxime (E) approached that of P2S, but even four fluorine
atoms had reduced the pKa to only 9.1.
2.2.2. Pentafluorobenzaldoxime I
Pentafluorobenzaldoxime (I) was isolated in 70% yield from
oximation of pentafluorobenzaldehyde (ex. C6F5MgBr + HCO2Et
[25]) (Scheme 9). It was prepared early on in the study to
demonstrate that a polyfluorinated aromatic carboxaldehyde was
capable of conversion to an oxime under standard conditions,
The suggestion that the high reactivation ability of 1-
methylpyridinium-2-aldoxime salts (P2S and 2-PAM) reflects
the ability of the quaternary nitrogen atom to bind to the anionic
site of inhibited AChE, orientating the oxime group towards the
phosphorus atom of the bound inhibitor [35], is difficult to

544
C.M. Timperley et al. / Journal of Fluorine Chemistry 132 (2011) 541–547
Table 1
Me
N
Me
Me
Porton screening data.
NO2
O2N
HNO3
Oxime
pKa
koxꢀ (l molꢀ1 minꢀ1
)
+
H2SO4
NH2
N
NH2
N
NH2
10.1
–
CH=NOH
58%
12a
12b
NaNO2
HCl
N
CH=NOH
F
9.8
1800
Me
Me
NO2
OH
O2N
+
N
N
13a
N
13b
OH
Cl
D
83%
POCl3
10.1
10.1
9.1
1690
1300
310
N
CH=NOH
P2A
Me
Me
F
NO2
Cl
O2N
+
N
CH=NOH
N
14a
N
14b
C
61%
H2, Pd/C
CH=NOH
F
Ph
F
H
H
Me
N
Me
F
N
F
F
F
NH2
PhCHO
EtONO
HBF4
E
KOAc
Ac2O
N
N
7.8
120
17 34%
16 53%
15 64%
N
CH=NOH
I
2 cat.
+
-
Me
P2S
i. O3
ii. H2
MeSO3
CHO
F
CH=NOH
F
H2NOH
EtOH
N
N
18 54%
oxime D 42%
Scheme 4.
F
CH=CHMe
CO2H
F
F
F
F
F
F
F
F
F
F
LiCH=CHMe
Et2O, -10°C
i. O3, EtOAc
ii. H2, Pd-BaSO4
N
N
F
N
F
19
20 85%
21 9%
33% yield
NaCN DMF
+
CN
CH=NH
F
CHO
F
F
F
F
F
F
F
F
H2O
Raney Ni-Al
HCO2H aq.
45% yield
N
F
N
F
N
F
22
23
24 61%
H2NOH EtOH
KF, 300°C, 20 h
71% yield
CN
CN
CH=NOH
Cl
Cl
Cl
Cl
H
H
H
H
F
F
F
PCl5, 350°C
Ni autoclave
N
N
N
F
25 71%
26
oxime E 45%
Scheme 5.

C.M. Timperley et al. / Journal of Fluorine Chemistry 132 (2011) 541–547
545
Me
F
Me
F
F
F
F
F
F
F
F
F
F
F
MeLi
Et2O, -10°C
LiCH=CHMe
Et2O, -10°C
N
CH=CHMe
N
N
28 79%
i. O3, EtOAc
ii. H2, Pd-BaSO4
19
27 88%
Me
Me
F
F
F
F
F
F
H2NOH
EtOH
N
CH=NOH
N
CHO
oxime F 51%
29 43%
Scheme 6.
F
CH=CHMe
F
(cf. P2A 10.1 ! P2S 7.8) and impart beneficial activity. Supporting
this idea is the finding that 3-fluoro-4-PAM reactivated (EtO)2-
P(O)OAChE in vitro much more efficiently than 4-PAM [12].
Although the screening method reported here was used in
the past at Porton to select compounds for in vivo evaluation,
direct reaction between an oxime and an organophosphorus
inhibitor is not relevant in vivo – reactivation of inhibited AChE
is the major mechanism of therapeutic action. To evaluate novel
oximes it is now common practice to investigate the kinetics of
reactivation of inhibited AChE before moving to in vivo models.
Caution must be exercised however, as the merit of reactivation
experiments lies not in their ability to predict the effectiveness
of treatment in vivo, but as an adjunct to such studies [38]. Also,
the pKa and formation of oximates is only one factor responsible
for the reactivating potency of oximes. The pKa value for P2S is
the same as that measured for obidoxime, which reactivates
F
F
F
F
F
2 LiCH=CHMe
Et2O, -10°C
N
19
F
N
CH=CHMe
30 85%
i. O3, EtOAc
ii. H2, Pd-BaSO4
CHO
CH=NOH
F
F
F
F
F
F
N
CHO
N
CH=NOH
31
oxime G
Scheme 7.
more efficiently AChE inhibited by
organophosphorus compounds [5,7]. Evidence has accumulated
to suggest that reversible -bonding of oximes to tryptophan
a broader range of
H
H
p
LiCH=CHMe
Et2O, -10°C
F
F
F
F
F
F
residues [3] in the AChE active site may help manoeuvre the
oximate anion towards the bound phosphorus residue. This
would suggest an improvement in reactivation with increasing
positive charge on the oxime ring; this effect may contribute to
the greater efficacy of 1-alkylpyridinium salts over their
unquaternized counterparts. Fluorine atoms should cause the
N
32
F
N
CH=CHMe
33
Scheme 8.
ring to become more electron-deficient and able to
p-bond
better (note that benzene (mp 6 8C) and hexafluorobenzene
(mp 4 8C) form a stable 1:1 complex (mp 24 8C) when mixed
[39]). Other oxime selection criteria are summarised elsewhere
[40].
Br
CHO
CH=NOH
F
F
F
F
F
F
F
F
F
H2NOH
EtOH
i. Mg, Et2O
ii. HCO2Et
F
F
F
3. Conclusions
F
34
F
F
35 38%
70%
oxime I
The pKa values of 3-fluoropyridine-2- and -4-aldoxime (C) and
(D) are too high for reactivation of inhibited AChE to occur in vivo.
Tetrafluoropyridine-4-aldoxime (E) has a koxꢀ value approaching
that of the good reactivator P2S, but suffers from the disadvantage
that even four fluorine atoms reduce the pKa to only 9.1. It seems
clear, however, that N-alkylation or the introduction of powerful
electron-attracting groups (e.g. CF3, CF2H, SF5, NO2, CN, CF3SO2 and
perhaps CF3CH2) as well as fluorine may lower the pKa to around
Scheme 9.
evaluate relative to the basicity and nucleophilicity of the oxime
group, because in most instances the inductive effect of the
quaternary nitrogen atom influences profoundly these properties.
Aldoximes with a pKa of 7.6–8.0 will be the best reactivators in vivo
the desired value of 8 while maintaining or improving the kox
ꢀ
regardless of oximate nucleophilicity or the presence of
a
figure. The historical data discussed herein should stimulate
further research into fluorinated oximes as countermeasures to NA
poisoning. Lines of development awaiting exploitation include
quaternization of the oximes described and investigation of their
ability to reactivate human AChE inhibited by a variety of nerve
agents.
quaternary nitrogen atom. A recent study comparing oxime pKa
with reactivity towards sarin confirmed that reactivity tails off as
the pKa exceeds 9 [36]. Although the fluorinated oximes screened
did not appear promising antidotes, N-alkylation, which seems
feasible [37], might reduce the pKa to a value useful for reactivation

546
C.M. Timperley et al. / Journal of Fluorine Chemistry 132 (2011) 541–547
4. Experimental details
4.7. Second-order rate constants (koxꢀ)
The carboxaldehydes featured in Schemes 2–9 have become
commercially available in recent years, so only procedures to the
oximes are described.
The reaction between aromatic aldoximes and sarin in aqueous
solution occurs by rate-controlling attack of the oxime anion at
the phosphorus centre with loss of HF, followed by rapid splitting
of the oxime phosphonate to give isopropyl methylphosphonic
acid. Second-order rate constants (koxꢀ) were derived using a
literature method [26] by measuring the rate of acid production in
KCl aq. (0.1 M) at 25 8C by continuous titration to constant pH with
sodium hydroxide. In the presence of a large excess of oxime, and
using equipment already described [26,27], the observed rate of
total acid-production was first order and proportional to the
oxime concentration and degree of ionisation (i) of the oxime
calculated from the Henderson–Hasselbalch equation, i.e. –
d[sarin]/dt = d[nH+]/dt = koxꢀ i[oxime][sarin] where n was the
number of moles of acid obtained per mole of sarin decomposed
(i.e. 2).
4.1. 2-Fluoropyridine-3-aldoxime (A)
A
solution of 2-fluoropyridine-3-carboxaldehyde (5.1 g,
40.8 mmol) in ethanol (10 ml) was added to hydroxylamine
hydrochloride (5.0 g, 71.9 mmol) in water (20 ml) basified with
2 M NaOH (5 ml). The mixture was heated under reflux for 15 min
and the product collected by filtration and sublimed (60 8C/
1 mmHg; 3.4 g, 60%). Mp 123 8C. Calcd. for C6H5FN2O: C, 51.4; H,
3.6; N, 20.0. Found: C, 51.1; H, 3.0; N, 19.8%.
4.2. 2-Fluoropyridine-6-aldoxime (B)
2-Fluoropyridine-6-carboxaldehyde (0.5 g, 4.0 mmol), hydrox-
ylamine hydrochloride (1.2 g, 17.3 mol) and 1 M NaOH (12 ml)
were heated under reflux for 20 min. The product that precipitated
upon cooling was collected by filtration and sublimed (60 8C/
1 mmHg, 0.4 g, 71%). Mp 153 8C. Calcd. for C6H5FN2O: C, 51.4; H,
3.6; N, 20.0. Found: C, 51.5; H, 3.6; N, 20.0%.
Acknowledgements
This paper is dedicated to the memory of Professor John Colin
Tatlow (1923–2008), a great ambassador for fluorine chemistry,
and a friend of many chemists. The authors thank the Ministry of
Defence UK for financial support. ßCrown Copyright 2011.
Published with permission of the Defence Science and Technology
Laboratory on behalf of the Controller of HMSO.
4.3. 3-Fluoropyridine-2-aldoxime (C)
3-Fluoropyridine-2-carboxaldehyde (0.7 g, 5.6 mmol) was
References
converted to oxime
C with difficulty using the technique
described in the previous section (0.3 g, 37%). Mp 85 8C. IR nmax
3070 (m), 2809 (m), 2789 (m), 1586 (m), 1495 (s), 1445 (s), 1318
(s), 1236 (m), 1152 (w), 1110 (w), 986 (m), 980 (m) and 803 (m)
cmꢀ1. Calcd. for C6H5FN2O: C, 51.4; H, 3.6; N, 20.0. Found: C, 51.3;
H, 3.6; N, 20.0%.
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21.7 mmol) in water (15 ml) basified with 2 M NaOH aq. The
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Pentafluorobenzaldehyde (0.4 g, 2.0 mmol) in ethanol (5 ml)
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