Short synthesis of 4-chloro-4′-(chlorodifluoromethoxy)benzophenone

Article abstract of DOI:10.1016/S0022-1139(99)00259-6

A one-pot, highly selective synthesis of 4-chloro-4′-(chlorodifluoromethoxy)benzophenone suitable for an industrial scale-up was developed. Fluorination of 4-(trichloromethoxy)benzoyl chloride at -20°C with HF to 4-(chlorodifluoromethoxy)benzoyl fluoride followed by an in situ Friedel-Crafts reaction with chlorobenzene in the presence of BF₃ at -5°C yielded the title compound in excellent yield.

Full text of DOI:10.1016/S0022-1139(99)00259-6

Journal of Fluorine Chemistry 103 (2000) 81±84
0
Short synthesis of 4-chloro-4 -(chlorodi¯uoromethoxy)benzophenone
a
Friedrich Karrer , Hans Meier , Alfons Pascual
Chemistry Research, Novartis Crop Protection, 4002 Basel, Switzerland
Hydrierung Hochdruck Services, Novartis Services Postbox, 4002 Basel, Switzerland
b
a,*
a
b
Received 10 September 1999; accepted 18 October 1999
Abstract
0
A one-pot, highly selective synthesis of 4-chloro-4 -(chlorodi¯uoromethoxy)benzophenone suitable for an industrial scale-up was
developed. Fluorination of 4-(trichloromethoxy)benzoyl chloride at ±208C with HF to 4-(chlorodi¯uoromethoxy)benzoyl ¯uoride followed
by an in situ Friedel±Crafts reaction with chlorobenzene in the presence of BF
2000 Elsevier Science S.A. All rights reserved.
3
at ±58C yielded the title compound in excellent yield.
#
3
Keywords: Chlorodi¯uorobenzene derivatives; Fluorination with HF/BF ; Friedel±Crafts reaction
1
. Introduction
In the course of our work on benzophenone hydrazone
second base was essential to obtain 2 by this process. This
method unfortunately showed serious drawbacks: the yields
were never higher than 40% and not reproducible and the
1
derivatives with insecticidal activity [1±6] we discovered the
excellent biological properties of some acylated 4-(perha-
loalkoxy)benzophenonehydrazones [7]. The interesting
results obtained with derivatives in the chlorodi¯uoro-
methoxy series 1 (see Fig. 1) prompted us to seek a con-
venient synthesis of the crucial intermediate benzophenone
2
present our work, which resulted in a short and easy synth-
esis of the hitherto unknown 4-chloro-4 -(chlorodi¯uoro-
methoxy)benzophenone 2.
puri®cation was tedious.
To ®nd an alternative to the above procedure we inves-
tigated the use of a Friedel±Crafts reaction. A notorious
problem associated with Friedel±Crafts reactions on
(haloalkoxy)benzenes is the halogen exchange reaction
caused by the Lewis acid, which leads to mixtures of
2
in view of a possible development process. Herein we
halogenated products. The benzoylation of (tri¯uoro-
methoxy)benzenes has been attempted [11] using AlCl3
as catalyst, conditions which cause halogen exchange and
0
degradation reactions, and BF in HF at 20±308C, which
3
gives excellent yields of the (tri¯uoromethoxy)benzophe-
nones. These latter reaction conditions are nevertheless
2
. Results and discussion
favourable to cause halogen exchange in a CF Cl group.
2
Interestingly, Friedel±Crafts reactions using (chlorodi¯uor-
omethoxy)benzene have never been described in the litera-
ture.
On the other side, we expected acyl derivatives of type 6
(see Fig. 3) to react under milder conditions at lower
We ®rst tried a route suitable for small-scale synthesis
0
starting from commercially available 4-chloro-4 -hydroxy-
benzophenone (3). Conversion of the OH group in simple
phenols to the OCF Cl group is described in the literature
2
(
with CHClF and consequent radical chlorination in [10])
with HF in CCl in [8], with HF and diphosgene in [9] and
4
2
essentially as a side reaction in the preparation of OCF3
derivatives. For this reason another method, the reaction of 3
with CCl F and CBrClF , was explored. After some opti-
misation work, we found the alkylation procedure outlined
in Fig. 2. Importantly, the use of potassium tert-butylate as
1
This is perhaps less surprising because the reaction of potassium
2 2 2
phenolates with CF Br and CF BrCl to form (bromodifluoromethoxy)-
2
2
2
benzenes, has been described to give low yields and low halogen
selectivity, see [21].
2
Halogen-exchange fluorinations with HF in the presence of electron
acceptors (especially pyridine) have been reviewed (see [22]). Olah et al.
[
23] have described formation of mixtures of C
OCClF upon treatment of (trifluoromethoxy)benzene with AlCl
Similar results were reported by Desbois ([11] and references therein).
6 5 2
H OCCl F and
C
6
H
5
2
3
.
*
Corresponding author. Fax. ‡41-6169782529.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 5 9 - 6

8
2
F. Karrer et al. / Journal of Fluorine Chemistry 103 (2000) 81±84
Fig. 1. Insecticidal benzophenone hydrazone derivatives 1 and intermediate 2.
Fig. 2. Small-scale synthesis of the benzophenone 2.
Fig. 3. Successful synthesis of 2.
temperature, thus minimising the formation of the unwanted
OCF compound 7. The synthesis of compound 6 from
Chlorination of the acid chloride 4 with Cl2 in the
presence of PCl at 2008C (chlorination of anisoles in
3
5
intermediate 5 would additionally bene®t from the fact, that
readily available ([12], chlorination of chlorothioformates
in [13], chlorination of anisoles in [14], with Cl /PCl and
[14]) gave 4-(trichloromethoxy)benzoylchloride 5 in excel-
lent yield. Subsequent ¯uorination of 5 with HF at low
3
temperature gave 6 in yields higher than 80%. Friedel±
2
3
irradiation in [15] and with CCl and irradiation in [16])
4
Crafts reaction of 6 in the presence of chlorobenzene using
HF/BF as Lewis acid yielded 2 in reasonable yields, but a
(
trichloromethoxy)benzenes can be transformed selectively
3
into (chlorodi¯uoromethoxy)benzenes using either HF or
SbF ([12], with HF in [17,18] and with SbF in [19,20]).
The preparation of acid ¯uoride 6 and its Friedel±Crafts
3
3
3
The preparation of this acid fluoride has been described from 5 using
excess HF at a temperature of 90±1008C [24]. This high reaction
temperature would in our opinion cause a considerable amount of
overfluorination.
reaction with chlorobenzene in HF with BF as Lewis acid
3
was consequently studied.

F. Karrer et al. / Journal of Fluorine Chemistry 103 (2000) 81±84
83
Table 1
a
Selected experiments
c
Ratio 2:7
Entry
Scale (mol)
Isolation of 6
Eq. of BF
3
Temperature of
addition of BF
Yield of crude
Percentage of
b
2 pure
3
(8C)
1
2
3
0.0089
0.0365
0.0830
Yes
Yes
No
18
12
6
0
0
68
76
95
45
60:40
85:15
98:2
d
NP
±5
69
a
Compare the experimental procedures.
b
c
d
3
With respect to 5; a high excess of BF does not increase the reaction rate but the building of side products and resinification.
19
Measured on the crude product by means of F NMR.
Not purified.
1
considerable amount of the tri¯uoromethoxy compound 7
was obtained as by-product (Table 1, entry 1). The reaction
conditions were systematically modi®ed and the most per-
tinent experiments are reported in Table 1. Lowering the
amount of BF improved the ratio OCF Cl:OCF (Table 1,
H NMR (CDCl , 250 MHz) d/ppm: 8.12 (d, 2H, J ˆ 8 Hz),
3
7.40 (d, 2H).
3.2. Friedel±Crafts experiments with 6, typical example
( see Table 1, entries 1 and 2)
3
2
3
entry 2). Making use of the fact that HF is used as solvent
and/or reagent in both steps (5 to 6 and 6 to 2), a one-pot
reaction 5 to 2 avoiding the isolation of the acid ¯uoride 6
was performed. Entry 3 in Table 1 shows then on decreasing
the amount of BF3 to 6 eq. (still ensuring a complete
conversion), using HF as solvent, and lowering the tem-
perature to below 08C, an excellent yield of 2 containing
only traces of 7 was obtained. Under these conditions, the
pernicious halogen exchange reaction C±Cl to C±F was
essentially suppressed.
Acid ¯uoride 6 (2.0 g, 8.9 mmol), chlorobenzene (1.12 g,
10.0 mmol) and CH Cl (10 ml) were introduced into a 0.3 l
autoclave and cooled to ±208C by means of an acetone/CO2
bath. HF (40 g) was introduced and the reaction brought to
2
2
08C. BF (11 g, 0.162 mol) was then added, whereupon the
3
internal end pressure reached 12 bar. The reaction was then
left at RT for 4 days (control by TLC and GC). Work up
analogous to the optimised procedure (see below) left 1.92 g
19
(68%) of crude material showing two peaks in the F NMR
spectrum (±28.3 ppm, ca. 60% and ±60.0 ppm, ca. 40%).
Flash-chromatography using ethyl acetate:hexane 1:20
yielded 1.25 g (45%) of a mixture of 2 and 7 as colourless
crystals melting at 55±588C (ratio 2±7 ca. 60±40).
3
. Experimental procedures
General. NMR spectra were recorded on a Bruker-AC-
F250 spectrometer using (CH ) Si or CF Cl as internal
3.3. Synthesis of 2, experimental optimised procedure (see
Table 1, entry 3)
3
4
3
standards. Mass spectra (EI-MS, 70 eV) were recorded
on a Finnigan MAT212. The melting points are uncorrected
and were determined on a Ko¯er apparatus. Solvents and
reagents were obtained from commercial sources and used
without further puri®cation. Stirring Monel 400 autoclaves
from Autoclave Europe were used. 4-(Trichloromethoxy)-
benzoylchloride (5) was prepared in 92% yield from com-
mercially available 4 according to the procedure of
Yagupolsky and Troitskaya (chlorination of anisoles in
4-(Trichloromethoxy)benzoyl chloride (5) (22.8 g,
0.083 mol) was introduced into a 0.3 l autoclave and
cooled to ±258C by means of an acetone/CO bath. Between
2
±25 and ±208C HF (100 g) was introduced into the autoclave
and after 10 min the reaction was allowed to warm to
RT overnight (total reaction time 21 h). The autoclave
was evacuated, the temperature brought down to ±58C
(Kryomat), and chlorobenzene (10.4 g, 0.092 mol) intro-
duced. Shortly afterwards BF3 (12.5 g, 0.184 mol) was
compressed into the autoclave (internal end pressure
10 bar) at ±58C. The reaction temperature was kept between
[
14]).
3.1. Preparation of 4-(chlorodifluoromethoxy)-
benzoylfluoride (6)
±
temperature and the HF distilled off. The crude material
5 and ±18C for 40 h. BF was then evacuated at this
3
4-(Trichloromethoxy)benzoyl chloride (5) (10.0 g,
6.5 mmol) was introduced into a 0.3 l autoclave and cooled
3
was poured onto ice and 50 ml CH Cl added. After separa-
2
2
to ±25 to ±208C by means of an acetone/CO bath. HF (50 g)
tion of the organic phase, the aqueous phase was extracted
three times with 50 ml CH Cl . The methylene chloride
extracts were washed with ice-water and dried over Na SO .
After removing the solvent on a rotary evaporator a dark
brown wax (25.0 g; NMR analysis: less than 2% of 7) was
obtained, which was stirred at 308C with 50 ml of a mixture
2
was condensed into the apparatus; then allowed to warm to
RT (18 h). The autoclave was evacuated and the excess HF
distilled off. The crude oily product 6 (7.4 g, 90%) was used
2
2
2
4
19
directly in the Friedel±Crafts experiments. F NMR
CDCl , 235 MHz) d/ppm: ±8.0 (COF), ±28.7 (CF Cl).
(
3
2

8
4
F. Karrer et al. / Journal of Fluorine Chemistry 103 (2000) 81±84
ethylacetate:hexane 1:10. A brown tar remained insoluble
and was discarded. The ®ltrate was cooled to 08C overnight,
and the formed colourless crystals were ®ltered off and
washed with a little cool hexane. From the concentrated
mother liquors upon addition of further hexane and cooling,
two further crops of crystals (identical to the ®rst by NMR)
were obtained. Yield of 2: 18.10 g (0.0572 mol, 69%). m.p.
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8
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2
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0
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[
4
A purer sample of 2 obtained by reaction of hydroxybenzophenone
3
with CCl
one peak at ±28.3 ppm in the F NMR spectrum.
2 2
F (compare Fig. 2) melted at 61±628C and showed only
19