Selective and efficient fluorination of chlorodiazines under solvent-free phase transfer catalysis

Article abstract of DOI:10.1016/j.jfluchem.2004.06.016

3-Chloro-6-phenylpyridazine, 2,3-dichloroquinoxaline and 1,4-dichlorophthalazine were reacted with KF under solvent-free conditions in the presence of a phase transfer agent, with or without microwave irradiation. The chlorine-fluorine exchanges were obta

Full text of DOI:10.1016/j.jfluchem.2004.06.016

Journal of Fluorine Chemistry 125 (2004) 1847–1851
www.elsevier.com/locate/fluor
Selective and efficient fluorination of chlorodiazines
under solvent-free phase transfer catalysis
a
Sylvain Marque , Hanane Snoussi , Andre Loupy ,
a
a,
*
´
b
Nelly Ple , Alain Turck
b
´
a
´ ´
Laboratoire des Reactions Selectives sur Supports, CNRS UMR 8615, ICMMO,
´ ˆ
Universite Paris-Sud, batiment 410, 91405 Orsay cedex, France
b
´ ´ ´
Laboratoire de Recherche en Chimie Fine et Heterocyclique, IRCOF, Universite de Rouen,
BP08, 76131 Mont Saint Aignan, France
Received 20 January 2004; received in revised form 14 February 2004; accepted 18 June 2004
Available online 11 September 2004
Abstract
3-Chloro-6-phenylpyridazine, 2,3-dichloroquinoxaline and 1,4-dichlorophthalazine were reacted with KF under solvent-free conditions in
the presence of a phase transfer agent, with or without microwave irradiation. The chlorine–fluorine exchanges were obtained with enhanced
yields and selectivities when compared with previous methods.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Chlorodiazines; Fluorination; Microwave activation; Solvent-free conditions
1. Introduction
crown-6 in THF with low to good yields (20–90%) [11].
Tetrabutylphosphonium hydrogendifluoride (Bu4P+, HF2
ꢀ
)
Diazines (x,y-diazabenzenes) are important compounds
having biological activity [1–3]. Among interesting deriva-
tives, fluorodiazines present the usual advantages of intro-
duction of fluorine atoms in terms of increased therapeutic
and agrochemical activities. They are involved in some
catalytic cross-coupling reactions of Kharash [4,5] type
reagents. They also constitute substrates of choice for
directed ortho-metallation reactions of diazines [6]. They
are accessible from chlorodiazines by nucleophilic aromatic
substitutions (SNAr) using fluorine as the nucleophile.
They were usually prepared by reacting KF in polar
aprotic solvents such as DMF or DMSO at 150 8C [7], or in
neat reaction conditions at 290–480 8C [8–10] for 8–20 h,
and leading to rather limited yields. Phase transfer catalysis
(PTC) was used in the case of SNAr reaction with
chloroquinoxalines by reacting CsF in the presence of 18-
was shown to give satisfactory yields (70–90%) when used
under solvent-free conditions at 80–140 8C for 2–100 h [12].
Finally, a mild and efficient reagent was recently advocated
comprising a combination of proton sponge (PS = bis a,a0-
dimethylaminonaphthalene)-triethylamine-hydrogen fluor-
ide. This mixture appeared capable of selective halogen
exchange or complete substitution of chlorine atoms in
(poly)chlorodiazines [13]. However, its drawbacks are its
high cost (PS), the handling of hazardous compounds (HF),
the extended delay for the preparation of this reagent and the
large reaction times from 2 to 7 days.
We describe here an improvement in conditions and
selectivities by using the solvent-free PTC technique, whose
potential was shown in some SNAr reactions on halopyr-
idines [14]. We have also checked the microwave activation
as especially efficient when coupled with solvent-free PTC
conditions [15], and yet tested in some fluorinations by SNAr
reactions in halopyridines [16,17].
* Corresponding author. Tel.: +33-1-69-15-76-50;
fax: +33-1-69-15-46-79.
As selected reactions have to be improved, we chose to
tackle the reactivity problem presented by the fluorination of
E-mail address: aloupy@icmo.u-psud.fr (A. Loupy).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.06.016

1848
S. Marque et al. / Journal of Fluorine Chemistry 125 (2004) 1847–1851
Table 1
Fluorination of 1 (5 mmol) under solvent-free PTC conditions and MW
activation
Entry
PTAa
Conversionb
Yieldc (%) in 4
1
2
3
4
a
18-crown-6
NBu4 HSO4
NBu4 Br
53
63
41
28
20
29
12
20
NBu4 Cl
Scheme 1.
Phase transfer agent (10% mol.equiv.).
b
c
Based on consumption of 1.
g.c. yields using an internal standard (dibutyl phthalate).
3-chloro-6-phenylpyridazine 1 and the reactivity and
selectivity aspects (mono and difluorination) characteristic
of 2,3-dichloroquinoxaline 2 and 1,4-dichlorophthalazine 3
(Scheme 1).
We first studied the influence of the PTA, fixing the
temperature at 150 8C, the reaction time at 1 h and using
1.5 eq. of KF (Scheme 2). The results are given in Table 1.
The best results were obtained with [n-Bu4]+[HSO4]ꢀ
and 18-crown-6 (entries 1 and 2), but ammonium salts are
prone to the decomposition at elevated temperature
(Hoffmann reaction); so, the influence of temperature and
reaction time using 18-crown-6 as the catalyst were
determined. The results are given in Table 2.
2. Results and discussion
All the reactions were carried out under solvent-free PTC
conditions, i.e. the chlorinated compound plays the dual
role of electrophilic reagent and organic phase for the
reaction. Cheap, safe and easy-to-handle KF was used as the
nucleophilic species in combination with a phase transfer
agent catalyst (PTA). Preliminary experiments without a
PTA failed completely; the conversion was less than 5% and
the yield negligible.
The best set of conditions is KF (1.3 eq.) for 1 h at 200 8C
(PTA: 18-crown-6). Using a simple solvent-free procedure
involving simple conditions (KF and 18-crown-6) [19], we
got a quantitative yield avoiding thus any further purifica-
tion. We have therefore improved noticeably the published
yields and conditions.
The reaction was also performed under conventional
heating, and we also obtained a quantitative yield.
For the sake of experimental simplification (no necessity
to preheat an oil or sand bath), reactions were carried out
using a monomode microwave (MW) reactor [18] at a fixed
temperature by modulation of emitted power. Results are
compared with those obtained with conventional heating
under similar conditions (vessels, time, temperature and
profiles of temperature rise).
2.2. Fluorination of 2
The fluorination of 2 is shown in Scheme 3.
2.2.1. Conditions for selective monofluorination
In the literature [13], this reaction was performed using
the mixture PS + NEt3ꢁ3HF in acetonitrile at 80 8C for 105 h
with a 57% conversion of 2, a 35% yield of 5 + 6 and with a
selectivity 5/6: 71/29.
All experiments were repeated at least twice and by
different workers.
2.1. Fluorination of 1
We studied the monofluorination under solvent-free PTC
conditions using 1 eq. KF and 18-crown-6 or TDA-1 [20] as
catalyst. The main results are given in Table 3.
This fluorination was twice described in the literature
[11,13], at 100 8C, using:
Two sets of conditions led to satisfactory yields and
selectivities. They involved either 18-crown-6 or TDA-1 as
catalyst within 1 h at 150 and 200 8C, respectively (entries
(i) PS + Et3Nꢁ3HF within 144 h, isolated yield = 63%
[13];
ꢀ
(ii) Bu4P+, HF2 within 2 h, g.c. yield = 89% [12].
Table 2
Fluorination of 1 (5 mmol) according to reaction time and temperature PTA
= 18-crown-6 (10%)
Entry
KF
Time
(min)
Temperature
Conversion
Yield
(eq.)
(8C)
(%) in 4
5
6
7
8
9
1.5
60
60
60
30
60
150
170
200
200
210
53
77
20
77
1.5
1.3 or 1.5
1.3
100
83
100
83
1.3
99
75
Scheme 2.

S. Marque et al. / Journal of Fluorine Chemistry 125 (2004) 1847–1851
1849
Scheme 3.
Table 3
Monofluorination of 2 (5 mmol) with KF (5 mmol) under solvent-free PTC conditions and MW activation
Entry
PTA (10%)
Temperature (8C)
Time (min)
Conversiona
Yieldb (%) in 5 + 6
5/6
10
11
12
13c
14
15
16
a
18-crown-6
18-crown-6
18-crown-6
18-crown-6
TDA-1
150
150
200
200
150
200
200
60
180
60
40
71
53
57
27
53
72
40
58
50
44
20
52
9
93/7
66/34
73/27
91/9
60
60
70/30
90/10
96/4
TDA-1
TDA-1
60
180
Based on consumption of 2.
g.c. yields using an internal standard (diethyl phthalate).
Using 50% of catalyst.
b
c
(i) PS (4 eq.)-NEt3ꢁ3HF (1.33 eq.) without solvent for 75 h
at 90 8C (5/6 = 12/88, total yield = 50%) [13];
(ii) CsF (8 eq.) + 18-crown-6 (1 eq.) in THF for 4 h at 65 8C
(5/6 = 0/100, yield = 64%) [11].
10 and 15). With respect to mono/difluorination (5/6),
selectivity was very good (ꢂ90/10) and yields acceptable for
such kind of reactions (40–52%). They constitute a large
improvement over previous experiments.
In order to compare the results of MW irradiation versus
conventional heating (D), the same reactions were
performed inside a thermostated oil bath under similar
conditions. Using 1 eq. KF and 10% TDA-1 for 1 h at
200 8C, the yields obtained under D and MW were
respectively 34 and 52%; the selectivity remained identical.
Specific (not purely thermal) MW effects were thus
highlighted in this special case and related to mechanistic
considerations [21]. An enhancement in the polarity of the
system from the ground state (GS) towards the transition
state (TS) was responsible for the observation of a specific
MW effect. It is consistent with the extension of anionic
charge delocalization in TS [22]. This implies an increase in
the polarity of the reaction system from GS to TS and
subsequent decrease in the energy of activation due to better
dipole–dipole coulombic interactions with TS.
We studied the effect of excess KF under solvent-free
PTC conditions. The results are given in Table 4.
The system KF (4 eq.) + 18-crown-6 (0.1 eq.) led
to a quantitative yield of 6 within 1 h at 200 8C. This
result constitutes a noticeable improvement over previous
published ones. Similar yields were obtained under either
MW or conventional heating inside a thermostated oil
bath, revealing no specific MW effects under these condi-
tions.
2.3. Fluorination of 3
The fluorination of 3 is shown in Scheme 4.
2.3.1. Conditions for selective monofluorination
In the literature [13], this monofluorination was realized
using PS + NEt3ꢁ3HF in acetonitrile at 85 8C for 96 h with a
yield of 37% (conversion in 3 = 86%) and a high selectivity
7/8 = 96/4.
2.2.2. Conditions for difluorination
This reaction has been studied twice in the literature
[11,13]:
Table 4
Difluorination of 2 (5 mmol) under solvent-free PTC conditions and MW activation
Entry
PTA (10%)
KF (eq.)
Temperature (8C)
Time (min)
Conversion
Yield (%) in 5 + 6
5/6
17
18
19
20
21
22
23
18-crown-6
TDA-1
5
5
5
5
4
3
2
200
200
200
150
200
200
200
60
60
30
60
60
60
60
100
90
100
90
0/100
40/60
2/98
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
99
79
99
94
2/98
100
100
93
100
97
0/100
7/93
84
32/68

1850
S. Marque et al. / Journal of Fluorine Chemistry 125 (2004) 1847–1851
Scheme 4.
Table 5
were enhanced within very short reaction times (usually 1 h
instead of several days). The method recommended here
involves a cheap and easy-to-handle fluorinating agent (KF)
in the presence of catalytic amount of 18-crown-6. It does
not use any solvent during the reaction as liquid chlorinated
diazines play both the role of electrophile and organic phase
for the reaction. In two cases, specific MW effects were
highlighted.
Monofluorination of 3 (5 mmol) under solvent-free PTC conditions (KF
1 eq. + 18-crown-6, 10%) and MW activation
Entry
Temperature
Time
(min)
Conversiona
Yieldb
7/8
(8C)
(%) in 7 + 8
24
25
26c
27
a
220
190
190
170
10
30
10
60
67
70
67
70
44
44
67
26
88/12
88/12
100/0
96/4
Based on consumption of 3.
g.c. yields using an internal standard (diethyl phthalate).
Using 1.2 eq. of KF.
b
c
4. Experimental
Table 6
4.1. Microwave equipment
Difluorination of 3 (5 mmol) under solvent-free PTC conditions (PTA = 18-
crown-6, 10%) and MW activation
Reactions were performed in a monomode reactor
Synthewave 402 (S 402) microwave device from Prolabo.
The temperature was measured during the reaction by
infrared detection, which indicates the surface temperature
after previous calibration of emissivity in each case with an
optical fiber thermometer (FTI-10 device from Fiso, optical
fiber up to 250 8C). The reactions were conducted in a
cylindrical Pirex tube with mechanical stirring to establish
homogeneity in temperature. The power was monitored
during irradiation to maintain constant temperature.
Entry KF (eq.) Temperature Time Conversiona Yieldb (%) 7/8
(8C)
(min)
in 7+8
28
29
30
31
5
220
205
220
220
5
5
5
5
100
100
100
85
83
90
98
63
1/99
8/92
3/97
86/4
5
4
2.2
a
Based on consumption of 3.
g.c. yields using an internal standard (diethyl phthalate).
b
The solvent-free system KF (1 eq.) + 18-crown-6
(0.1 eq.) was tested under different conditions. The results
are given in Table 5.
Commercial diazines were used without purification.
Solid 18-crown-6 ether was stored under vacuum over P2O5.
Other PTCs were used without any purification. Potassium
fluoride was used without any purification and drying.
Under the conditions of entry 26, monofluorination was
accomplished with complete selectivity.
2.3.2. Conditions for difluorination
4.2. Typical experiment for MW reactions
(2,3-difluoroquinoxaline)
The reaction time was fixed at 5 min and the temperature
and the amount of KF were varied. The main results are
given in Table 6.
Nine hundred and ninety five milligrams of 2,3-dichloro-
quinoxaline 2 (5 mmol), 1162 mg of potassium fluoride
(20 mmol, 4 eq.) and 133 mg of 18-crown (0.5 mmol, 0.1 eq.)
were placed in the reactor. The reaction was performed in
an open vessel. The mixture was irradiated in the S 402 with
mechanical stirring for 1 h and at 200 8C. After the
irradiation time, the temperature was controlled with the
optical fiber thermometer, and then the reactor was cooled
down to room temperature. The materials were filtered on
Celite 545 under vacuum with 50 mL of ethyl acetate. A
sample (1/10th) of the crude mixture was analyzed by gas
chromatography. Conversion and yield were determinated
by the internal standard method to give 830.5 mg of 2,3-
difluoroquinoxaline 6 (100% GC yield). Experiments
A very good result (yield = 98%, selectivity = 3/97) was
obtained using 4 eq. KF for 5 min at 220 8C.
The best experiment was carried out under conventional
heating with similar conditions. We got an 83% yield and a
ratio of 7/8 = 38/62 which revealed a large MW specific
effect on reactivity, and which also affected the relative
amounts of di/monofluorinated products.
3. Conclusion
Solid–liquid solvent-free PTC leads to noticeable
improvements over published conventional methods. Yields

S. Marque et al. / Journal of Fluorine Chemistry 125 (2004) 1847–1851
1851
leading to quantitative yields have been reproduced at least
twice.
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4
5
6
7
3-Fluoro-6-phenylpyridazine
2-Fluoro-3-chloroquinoxaline
2,3-Difluoroquinoxaline
1-Fluoro-4-chlorophthalazine
1,4-Difluorophthalazine
Diethyl phthalate
7.47
4.37
2.45
4.80
7.25
7.88
12.05
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8
Internal standard
Internal standard
Dibutyl phthalate