Novel method for preparing fluorination reagent and its application to synthesis of fluoropyridazinones

Article abstract of DOI:10.1080/00397910903003466

4-Chloro-5-fluoro-2-aryl-3(2H)-pyridazinones were obtained by the fluorination of 4,5-dichloro-2-aryl-3(2H)-pyridazinones with ethylhexamethylenetetramine fluoride in excellent yields. The ethylhexamethylenetetramine fluoride was synthesized by the reacti

Full text of DOI:10.1080/00397910903003466

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Novel Method for Preparing Fluorination
Reagent and Its Application to Synthesis
of Fluoropyridazinones
Wen Pei a & Wei Yang a
a College of Chemical Engineering and Materials , Zhejiang
University of Technology , Hangzhou, China
Published online: 03 Feb 2010.
To cite this article: Wen Pei & Wei Yang (2010) Novel Method for Preparing Fluorination
Reagent and Its Application to Synthesis of Fluoropyridazinones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:4, 535-539, DOI:
10.1080/00397910903003466
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Synthetic Communications1, 40: 535–539, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903003466
NOVEL METHOD FOR PREPARING FLUORINATION
REAGENT AND ITS APPLICATION TO SYNTHESIS
OF FLUOROPYRIDAZINONES
Wen Pei and Wei Yang
College of Chemical Engineering and Materials, Zhejiang University
of Technology, Hangzhou, China
4-Chloro-5-fluoro-2-aryl-3(2H)-pyridazinones were obtained by the fluorination of
4,5-dichloro-2-aryl-3(2H)-pyridazinones with ethylhexamethylenetetramine fluoride in
excellent yields. The ethylhexamethylenetetramine fluoride was synthesized by the reaction
of hydrofluoric acid with ethylhexamethylenetetramine hydroxide prepared from ethyl-
hexamethylenetetramine bromide and alkali.
Keywords: Ethylhexamethylenetetramine fluoride; fluorination; halopyridazinones; onium fluorination
reagent
INTRODUCTION
Fluoropyridazine compounds are important intermediates of pharmaceuticals
and herbicides for their good biological activities.[1] The research on the pyridazine
chemistry has been developed rapidly since Fischer obtained a pyridazine compound
in 1886. However, there had been less thorough investigation of the fluoropyridazine
system than about other pyridazine systems before the antitumor activity of fluoro-
pyrimidine derivatives was discovered. Following fluoropyrimidine research, the field
of fluoropyridazine chemistry has attracted much attention from organic chemists
for its biological activities, such as herbicidal, antituberculosis, and antitumor
activities.
In the field of fluoropyridazinones, the limited solubility and poor reactivity of
metal fluorides such as potassium fluoride has led to the search for more soluble and
more reactive Fluoride sources. A number of nonmetal reagents have been reported,
including ammonium fluorides (notably nBu4NF[2,3] and Me4NF[4,5]) and phos-
phonium fluorides,[6,7] as well as more active forms of metal fluorides such as CsF
and supported fluorides.[8,9] Unfortunately, there are significant drawbacks with
all known fluoride reagents. The more soluble and reactive reagents such as nBu4NF
can be thermally unstable and impossible to dry, while the essentially heterogeneous
reagents suffer from rather poor activity. This means that there is a continuing need
Received February 8, 2009.
Address correspondence to Wen Pei, College of Chemical Engineering and Materials, Zhejiang
University of Technology, Hangzhou 310014, , China. E-mail: peiwen58@zjut.edu.cn
535

536
W. PEI AND W. YANG
for new sources of fluoride ions. As part of our continued interest in exploring new
way of synthesizing fluorination reagents, we report the synthesis of ammonium
fluoride with hexamethylenetetramine (which is widely used as a reagent in organic
synthesis[10]) as a precursor. In this work, we discuss in detail the preparation of
onium fluoride and its special value in fluorination reactions of fluoropyridazinones.
RESULTS AND DISCUSSION
The previously mentioned fluorination reagent 4 can be synthesized by simply
mixing 2 with silver fluoride.[11] However, silver fluoride was unstable and expensive
and is prepared from hydrofluoric acid. At the same time, the yield was poor (only
5%) when 2 directly reacted to hydrofluoric acid. So, we proposed an improved
method for synthesizing 4. In view of the strong nucleophilic property of the hydroxy
group in base and weak nucleophilic property in acid, the process of hydroxy group’s
substitution with to bromide and substituted by fluoride ion came into reality. After
a two-step sequential anion exchange, 2 was changed into product 4 in 74% yield. It
is advantageous to utilize potassium hydroxide and hydrofluoric acid as reactant
instead of silver fluoride, because of simpler operations, better yields, lower cost,
and vast starting materials. Furthermore, the fluorination reagent can be recycled
and reused in the reaction by treatment with alkali, followed with hydrofluoric acid.
(The amount of fluoride ion was analyzed by a fluoride ion electrode see Scheme 1).
Then, we carried out a fluorination experiment with newly prepared 4 as fluor-
ination reagent. First, 4,5-dichloro-2-phenyl-3(2H)-pyridazinone was used as model
substrate to react with fluorination reagent in dimethylsulfoxide (DMSO) (Scheme 2,
Table 1). The fluorination did proceed to give the desired product 6a in 66% yield
when 5a was treated with 2 mol equiv. of potassium fluoride in anhydrous DMSO
at 80ꢀC for 6 h (entry 1). With catalysis of Me4NF, the yield of 6a was 48% (entry
2). So far, the best result was obtained by using 4 as fluorination reagent, which gave
6a in 93% yield (entry 3).
Encouraged by the success of fluorination of 4, we next examined the direct
synthesis of 6a from 5a by 4. The one-pot procedure treatment of 5a with 2 mol
Scheme 1. Procedure for preparation of ethylhexamethylenetetramine fluoride.
Scheme 2. Fluorination of 4,5-dichloro-2-phenyl-3(2H)-pyridazinone.

SYNTHESIS OF FLUOROPYRIDAZINONES
537
Table 1. Optimization of reaction conditions for fluorination of 5aa
Entry
Fluorination reagent
Solvent
T (ꢀC)
Yieldb (%)
1
2
KF
Me4NF
DMSO
DMSO
100
100
100
20
66
48
93
3
EtHMTAF
DMSO
<5
83
80
120
100
100
72
53
4
5
EtHMTAF
EtHMTAF
DMF
CH3CN
<5
aReaction conditions: 5a (1 mmol), fluorination reagent (2 mmol), solvent (10 mL), 8h.
bIsolated yield.
equiv. of 4 in DMSO at 100ꢀC for 8 h gave desired product 6a in 93% yield (Table 1,
entry 3). In this section, the effects of solvents on the reaction were particularly
investigated (Table 1). We found that the reaction proceeded well in polar aprotic
solvents. DMSO was a satisfying solvent (entry 3), whereas CH3CN and dimethyl-
formanide (DMF) were proven to be poor for the reaction (entries 4 and 5).
Finally, a range of 4,5-dichloro-2-aryl-3(2H)-pyridazinones were tested in the
one-pot synthesis of 6 from 5 by EtHMTAF at 80–120ꢀC in DMSO (Scheme 2,
Table 2). In most cases, the reaction proceeded smoothly to give 6 with excellent
yield. Nitro-substituted aromatic pyridazinone possessing electron-donating groups
(entry 2) generally gave better yield of 6 than those containing electron-withdrawing
groups (entries 3 and 4).
In conclusion, we have developed a novel and convenient procedure for the
synthesis of ethylhexamethylenetetramine fluoride and proved its efficiency for
synthesizing fluoropyridazinones. The new synthesis of ethylhexamethylenetetra-
mine fluoride cannot only provide increased yields, simpler operations, and cheaper
raw materials but also expand the accessible chemical space of the formed fluorina-
tion reagent.
EXPERIMENTAL
General
Melting points were uncorrected. 1H NMR spectra were obtained on a Bruker
AC 400 (400-MHz) instrument in CDCl3 using tetramethylsilane (TMS) as internal
standard. Infrared (IR) spectra were taken with a Bruker Victor 22 spectrometer.
Mass spectra (MS) were obtained on an HP 5989B mass spectrometer. Elemental
analyses were performed on an EA-1110 instrument.
General Procedure for the Fluorination
A three-necked, round-bottomed flask containing a stirring bar was charged
with halopyridazinones (1.0 mmol), ethylhexamethylenetetramine fluoride (2.0 mmol),

538
W. PEI AND W. YANG
Table 2. Synthesis of fluoropyridazinones from ethylhexamethylenetetramine fluoride
Entry
R
Time (h)
Producta
Mp (ꢀC)
Yield (%)b
1
2
3
4
C6H5
8
8
6a
6b
6c
6d
141–142
203–204
103–104
70–71
93
95
87
72
4-NO2C6H4
2-CH3C6H4
CH2C6H5
10
12
aAll products were characterized by 1H NMR, MS, and IR.
bIsolated yields.
and DMSO under nitrogen at 100ꢀC and monitored (by thin-layer chromatography,
TLC) until completion. Water (20 mL) was added; after being cooled, the mixture was
extracted with CH2Cl2 (3 ꢁ 20 mL). Then the organic layer was combined and washed
with water, dried with MgSO4, filtered, and concentrated in vacuo. The product was
purified by flash chromatography on silica gel using ethyl acetate and petroleum ether
(1:3 in volume ratio) as eluant. The structure of the compound was confirmed by
1H NMR, MS, and melting point. The physical and spectral data of the compounds
are as follows.
Selected Data
4-Chloro-5-fluoro-2-phenyl-3(2H)-pyridazinone (6a). Mp 141–142ꢀC
1
(lit.[2]145–146ꢀC). H NMR (400 MHz, CDCl3) d: 6.96–7.26 (m, 5H, Ph), 7.91 (s,
1H); 19F NMR (CDCl3) d: 32; IR (KBr) n 1640, 1606 cmꢂ1; MS m=z: 224 (Mþ).
Anal. calcd for C10H6ClFN2O: C, 53.57; H, 2.68; N, 12.50. Found: C, 53.67; H,
2.55; N, 12.61.
4-Chloro-5-fluoro-2-(4-nitrophenyl)-3(2H)-pyridazinone (6b). Mp 203–204ꢀC
(lit.[12] 201ꢀC). IR (KBr) n 1675, 1620 cmꢂ1; MS m=z: 269 (Mþ). Anal. calcd. for
C10H5ClFN3O3: C, 44.53; H, 1.86. Found: C, 45.01; H, 1.96.
4-Chloro-5-fluoro-2-(2-methylphenyl)-3(2H)-pyridazinone (6c). Mp 103–104ꢀC
(lit.[12] 106ꢀC). IR (KBr) n 1640, 1565 cmꢂ1; MS m=z: 238 (Mþ). Anal. calcd. for
C11H8ClFN2O: C, 55.35; H, 3.35. Found: C, 55.85; H, 3.65.
4-Chloro-5-fluoro-2-benzyl-3(2H)-pyridazinone (6d). Mp 70–71ꢀC (lit.[12]
1
72–73ꢀC). H NMR (400 MHz, CDCl3) d: 4.29 (s, 2H), 7.56–7.96 (m, 5H, Ph),
8.03 (s, 1H); IR (KBr) n 1640, 1610 cmꢂ1; MS m=z: 238 (Mþ). Anal. calcd. for
C11H8ClFN2O: C, 55.35; H, 3.35. Found: C, 55.37; H, 3.40.

SYNTHESIS OF FLUOROPYRIDAZINONES
539
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