Preparation of Trifluoromethylphenyl Magnesium Halides in the Presence of LiCl and Synthesis of 2′-Trifluoromethyl-Aromatic Ketones

Article abstract of DOI:10.1021/acs.oprd.6b00200

The effect of LiCl-promoted insertion of magnesium turnings into halogenated-trifluoromethylbenzenes for Grignard reagent synthesis was investigated. In the presence of less than 1.0 equiv of LiCl, chloro(trifluoromethyl)benzene Grignard reagents were easily generated. The 2-trifluoromethylphenyl magnesium chloride Grignard reagent was obtained in high yield and 2′-trifluoromethyl-substituted aromatic ketone was synthesized through reaction of the obtained Grignard reagent with a carboxylic anhydride in an 83% yield.

Full text of DOI:10.1021/acs.oprd.6b00200

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Full Paper
Preparation of Trifluoromethylphenyl Magnesium Halides in the
Presence of LiCl and Synthesis of 2#-Trifluoromethyl-Aromatic Ketones
Jiro Nakatani, and Tatsuhiro Nozoe
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00200 • Publication Date (Web): 25 Aug 2016
Downloaded from http://pubs.acs.org on August 28, 2016
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Preparation of Trifluoromethylphenyl Magnesium Halides in the Presence of
LiCl and Synthesis of 2′ꢀTrifluoromethylꢀAromatic Ketones
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Jiro Nakatani* and Tatsuhiro Nozoe
Electronic & Imaging Chemical Materials Technology Development Dept., Toray Fine
Chemicals Co., Ltd. 1ꢀ1, Katsube 6ꢀchome, Moriyama, Shiga 524ꢀ0041, Japan
jiro_nakatani@tfc.toray.co.jp
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Table of Content
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Grignard Reagent Synthesis
Aromatic Keton Synthesis
CF3
CF3
CF3
LiCl
0.3 equiv)
(
(RCO) O
O
2
X
+
Mg
MgX
R
X= Cl, Br
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ABSTRACT
The effect
of
LiClꢀpromoted
insertion
of
magnesium
turnings
into
halogenatedꢀtrifluoromethylbenzenes for Grignard reagent synthesis was investigated. In the
presence of less than 1.0 equivalent of LiCl, chloro(trifluoromethyl)benzene Grignard reagents
were easily generated. The 2ꢀtrifluoromethylphenyl magnesium chloride Grignard reagent was
obtained in high yield and 2'ꢀtrifluoromethylꢀsubstituted aromatic ketone was synthesized
through reaction of the obtained Grignard reagent with a carboxylic anhydride in an 83% yield.
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Keyword: Grignard reagents synthesis, Halogenated benzotrifluorides, LiCl Aromatic ketone,
INTRODUCTION
In general, aromatic ketones are synthesized using a FriedelꢀCrafts reaction where aromatic
substrates react with acyl halides or carboxylic anhydrides in the presence of a Lewis acid such
1
as aluminum chloride; however, this reaction is limited to the acylated position on the aromatic
ring. Moreover, aromatic ketones are difficult to obtain using the FriedelꢀCrafts route in cases
where the substrate contains a strong electron‐withdrawing group that reduces its reactivity.
When trifluoromethylbenzene is used as the substrate, orthoꢀ and paraꢀacylated
trifluoromethylbenzene are difficult to obtain because acylation occurs at the metaꢀposition.
Therefore, methods other than the FriedelꢀCrafts reaction is required when orthꢀ or paraꢀacylated
2
trifluoromethylbenzene is desired.
3
The ferrocenyl ketones are obtained via the in situꢀganerated mixed anhydride;
however,the method has problems in their industrial use from the viewpoint of the handling on
corrosive substance and inexpensive method because an equimolar amount of trifluoroacetic
anhydride is necessary.
The synthesis of 3,5ꢀbis(trifluoromethyl)acetophenone was examined through the reaction of
a Grignard reagent derived from 3,5ꢀbis(trifluoromethyl)bromobenzene with acetic anhydride. In
a previous report, the Grignard reagent was not obtained with Mg turnings due to poor reactivity;
therefore, highly reactive Mg dust or a metalꢀhalogen exchange method with iPrMgBr was used
in the Grignard reagent synthesis. However, halogenated trifluoromethylbenzenes can react
5
dangerously with Mg dust. Moreover, the Grignard reagent decomposition caused by instability
6
occurred with a strong exothermic reaction.
Knochel et al. found that LiCl mediates metal insertion reactions of aryl halides using zinc
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powder. LiCl likely increases the solubility of the formed organozinc compound, supplies a
clean metal surface due to the formation of a LiClꢀcomplex Grignard reagent, aids in
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electrophilic activation of aromatic compound, facilitates charge separation from the high ionic
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strength of LiCl, and accelerates metal insertion. Recently, LiCl was reported to promote
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preparation of aryl magnesium reagents, as well as aryl zinc halides. In the presence of LiCl
(
1.25 equivalent) in THF at 0 °C, safe and rapid magnesium insertion into
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ꢀboromo(trifluoromethyl)benzene proceeds with magnesium turnings, and the obtained
Grignard reagent is stable. Moreover, the Grignard reagent was crossꢀcoupled with ethyl
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4
ꢀiodobenzoate, resulting in the biphenyl derivative with high yield. Studer et al. reported that
using a Sonogashiraꢀtype crossꢀcoupling reaction with an aryl Grignard reagent complexed with
LiCl and an alkynyl Grignard reagent, orthoꢀsubstituted aryl compounds are obtained in high
1
0
yield; however, there are still few studies reporting on the effects of LiCl on Grignard reagent
synthesis and the reaction of aryl Grignard reagents complexed with LiCl.
Herein, we report the effect of LiClꢀpromotion and the position of halogenꢀsubstituted
trifluoromethylbenzene on Grignard reagent synthesis. Furthermore, the reaction of the
synthesized Grignard reagent with carboxylic anhydrides to form trifluoromethylꢀsubstituted
aromatic ketones was examined.
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RESULTS AND DISCUSSION
Although aromatic chlorides are generally less expensive and more available than bromides,
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aromatic chlorides are less reactive. The halogenated trifluoromethylbenzenes in this study
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exhibit the same behavior.
Table 1. Grignard reagent synthesis from bromo(trifluoromethyl)benzenes (BTFBs).
CF3
CF3
Br
+
Mg
MgBr
THF
BTFB
1a : ortho-, 1b : meta-, 1c : para-
LiCl/Substrate
(molar ratio)
Conversion
(%)
Product
Yield
(%)
Entry
Substrate
1
2
3
4
5
6
orthoꢀBTFB
orthoꢀBTFB
meta ꢀBTFB
meta ꢀBTFB
para ꢀBTFB
para ꢀBTFB
ꢀ
～100
～100
～100
～100
～100
～100
1a
1a
1b
1b
1c
1c
98
98
97
96
90
93
0.3
ꢀ
0.3
ꢀ
0.3
Conditions: THF/Mg = 5.0 (molar ratio), Mg/substrate = 1.04 (molar ratio), reaction temp. 40
°C, time = 4 h
The bromo(trifluoromethyl)benzenes (BTFBs) in this study were readily transformed into
Grignard reagents, regardless of the position of bromine substituent. The presence of LiCl was
not observed to affect the rate of formation or the yield of the Grignard reagent, which is likely
due to the high reactivity of the BTFBs. Therefore, it can be noted that LiCl is not always
necessary for Grignard reagents synthesis of BTFBs. In case of paraꢀBTFB, which is reported to
be unstable and highly reactive, a decrease in the yield of the Grignard was observed due to
formation of 4,4′ꢀbis(trifluoromethyl)biphenyl, the homoꢀcoupled Grignard reagent (Table 1,
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entries 5, 6).
Table 2. Grignard reagent synthesis from chloro(trifluoromethyl)benzenes (CTFBs)
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1
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CF3
Cl
+
Mg
MgCl
THF
CTFB
2a : ortho-, 2b : meta-, 2c : para-
LiCl/Substrate
Temp
( °Cꢀ)
Time
( h )
Conversion Product
(%)
Yield
(%)
Entry
Substrate
(molar ratio)
1
2
3
4
5
6
7
8
orthoꢀCTFB
meta-CTFB
para ꢀCTFB
orthoꢀCTFB
orthoꢀCTFB
orthoꢀCTFB
meta ꢀCTFB
para ꢀCTFB
ꢀ
50
4
7
7
4
4
4
7
7
91
62
0
2a
2b
2c
2a
2a
2a
2b
2c
90
60
ー
97
98
97
86
49
ꢀ
50
ꢀ
50
0.3
0.5
1.0
1.0
1.0
50
98
99
98
94
51
50
50
50
50
Conditions: THF/Mg = 5.0 (molar ratio), Mg/substrate = 1.04 (molar ratio).
In case of chloro(trifluoromethy)lbenzenes (CTFBs), the reactivity was found to depend
on the position of chloro substituent (Table 2, entries 1–3). An exothermic reaction was observed
as soon as drops of orthoꢀCTFB were added into the activated Mg tunings in THF at 50 °C.
orthoꢀCTFB was converted to a Grignard reagent with 90% yield after 4 h. In contrast,
metaꢀCTFB did not exhibit an exothermic reaction and the rate of metal insertion is slower than
that of orthoꢀCTFB. After a 7 h reaction time, ~40% substrate remained (Table 2, entry 2). In the
case of paraꢀCTFB, the reaction did not proceed, even after intense stirring for 7 hours (Table 2,
entry 3).
On the other hand, it is conformed that in the presence of LiCl in THF, the rate of
Grignard reagent formation for orthoꢀ, metaꢀ, and paraꢀCTFBs considerably increases (Table 2,
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entries 4–6). orthoꢀCTFB was transformed into the Grignard reagent after 4 h in more than 97%
yield. The reaction promoting effect can be achieved using only 0.3 equivalent of LiCl, which is
less than the relative equivalent of the substrate used. Furthermore, LiCl was seen as a precipitate
in the solution after the reaction when more than 1.0 equivalent was used, indicating that less
than an equivalent of LiCl is sufficient.
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DSC analysis (nitrogen sealed stainlessꢀsteel pressureꢀresistant cell) was performed on the
prepared Grignard reagent 2a, as shown in Table 2, entry 4. The onset temperature of exothermal
behavior is 115 °C and the calorific value is 95 J/g. Intense decomposition behavior was not
observed. The stability of 2a may be improved by the presence of LiCl.
The metaꢀCTFB was transformed into 2b in a 60% yield in the absence of LiCl after 7 h. In
contrast, the yield reached 86% in the presence of LiCl (Table 2, entries 2, 7).
In the case of paraꢀCTFB, the reaction did not proceed in the absence of LiCl, but formed 2c
in a 49% yield after 7 h in the presence of 1.0 equivalent of LiCl (Table 2, entry 8).
The presence of LiCl on Grignard formation with CTFBs, and particularly orthoꢀCTFB,
resulted in the formation of the desired products, confirming the reaction promoting effect of
LiCl; however, although the reaction promoting effect was observed with metaꢀ and
paraꢀCFTBs, the reaction rate is still insufficient for industrialization.
Furthermore, formation of trifluoromethylꢀsubstituted aromatic ketones through coupling with
carboxylic anhydrides was examined using the obtained Grignard reagents (2a : Table 2, entry 4;
1b : Table 1, entry 4; and 1c : Table 1, entry 6).
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Table 3. Synthesis of aromatic ketones substituted with a trifluoromethyl group.
CF3
CF3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3a : ortho-, R=CH3
O
R
4a : ortho-, R=C H5
2
5
3
a : ortho-, R=C H7
+
(RCO) O
MgCl
2
3b : meta-, R=CH3
3
c : para-, R=CH3
R= CH , C H or C H
7
3
2
5,
3
b)
a)
Yield
%)
Entry Grignard reagent Carboxylic anhydride Product
(
1
2
3
4
5
6
2a
↑
↑
1a
1b
1c
(CH CO) O
3a
4a
5a
3a
3b
3c
83
73
74
83
52
35
3
2
(C H CO) O
2
5
2
(C H CO) O
3
7
2
(CH CO) O
3
2
(CH CO) O
3
2
↑
Reaction conditions: reaction temp. 30 °C, time 2 h
a) Carboxylic anhydride/substrate = 1.5 (mol/mol)
b) Calculated with respect to substrate
The reaction of 2a with carboxylic anhydride to 2'ꢀtrifluoromethyl aromatic ketones
proceeded rapidly under the mild conditions in a 70% yield, regardless of the identity of the
carboxylic anhydrides (Table 3, entries 1–3) and the yield of 2'ꢀtrifluoromethyl aromatic ketones
was the same (Table 3, entries 1, 4).
In case of 1b or 1c, the yield substantially decreased compared to 2a. The reaction of these
Grignard reagents (1b or 1c) with carboxylic anhydrides yielded byproducts (Scheme 1,
compounds 6 and 7), which were identified by GCMS analysis. Compound 6 was formed
through reaction of the desired aromatic ketone with additional Grignard reagent, and compound
7
was formed through reaction of 6 with additional carboxylic anhydride.
The higher yield of 2'ꢀtrifluoromethyl aromatic ketones compared to 3′ꢀ or
′ꢀtrifluoromethyl aromatic ketones is likely due to steric interference by the trifluoromethyl
4
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group next to the acyl group, that is, 3′ꢀ or 4′ꢀtrifluoromethyl aromatic ketones are subjected to
attack by the Grignard reagent as indicated below (Scheme 1). Conversely, 2'ꢀtrifluoromethyl
aromatic ketones are hard to recieve the attack of the Grignard reagent.
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CF3
O
CF3
MgX
R
F3C
F3C
OH
(RCO) O
2
O
R
CF3
O
CF3
R
R
6
7
Scheme 1. Formation of byproducts
Table 4. Optimization of the reaction temperature on formation of
2
′ꢀtrifluoromethylpropiophenone
CF3
CF3
O
MgCl
+
(C H CO) O
2 5 2
4a
a)
Temp
Yield
(%)
Entry
(
°C )
1
2
3
4
10
83
80
71
67
30
50
60
Reaction conditions: carboxylic anhydride/substrate = 1.0 (mol/mol), reaction time 2 h
a) Calculated with respect to substrate
The influence of the reaction temperature was investigated for the synthesis of
2
'ꢀtrifluoromethylpropiophenone 4a through reaction with 2a and propionic acid anhydride.
When the temperature was more than 50 °C, the yield of 4a was reduced, due to the formation of
byproducts 6 and 7.
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Formation of 4a using Grignard reagents and propionic anhydride was found to be controlled
by low reaction temperatures. 4a was obtained after quenching the reaction with an aqueous
solution, washing with aqueous NaCl, and distillation using a filling tower (number of theoretical
plates = 3). Total yield was 59% and the purity was found to be 99.6% (GC area %) as a clear,
colorless oil.
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EXPERIMENTAL SECTION
Grignard reagent synthesis (General Procedure)
1 mol/L EtMgBr/THF solution (0.5 g) was added to a mixture of Mg turnings (5.1 g, 0.208
mol), LiCl (2.54 g, 0.06 mol) and THF (75.0 g) under nitrogen gas flow (for removing water) in
a 200 mL flask at room temperature. EtBr (0.44 g, 0.004 mol) was added for removing the oxide
film from the surface of the Mg turnings with a slight increase in temperature.
1ꢀchloroꢀ2ꢀ(trifluoromethyl)benzene (36.1 g, 0.2 mol) was added gradually using a dropping
funnel to the mixture at ~50 °C; furthermore, the reaction mixture was stirred at 50 °C for 4 h to
obtain the Grignard reagent. The reaction mixture was then diluted with toluene (10.8 g). A
sample of the solution was hydrolyzed with a saturated aqueous ammonium chloride solution,
and GC analysis was performed on a diethyl ether abstracted solution from that sample. The
conversion
ꢀchloroꢀ2ꢀ(trifluoromethyl)benzene.
Coupling with acid anhydride (General Procedure of 4a)
and
yield
were
calculated
relative
to
the
amount
of
1
The Grignard reagent was gradually added using a dropping funnel into a solution of
propionic anhydride (26.0 g, 0.2 mol) and toluene (43.3 g) at 30 °C in a 200 mL flask under N2
flow in a water bath. Furthermore, the reaction mixture was stirred at 30 °C for 2 h. A sample of
the solution was analyzed by GC. The yield was calculated relative to the amount of
1ꢀchloroꢀ2ꢀ(trifluoromethyl)benzene.
Coupling with acid anhydride (General Procedure of 3a)
The Grignard reagent was gradually added using a dropping funnel into a solution of acetic
anhydride (20.6 g, 0.2 mol) and toluene (43.3 g) at 30 °C in a 200 mL flask under N flow in a
2
water bath. Furthermore, the reaction mixture was stirred at 30 °C for 2 h. A sample of the
solution was analyzed by GC. The yield was calculated relative to the amount of
1ꢀchloroꢀ2ꢀ(trifluoromethyl)benzene.
Coupling with acid anhydride (General Procedure of 5a)
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The Grignard reagent was gradually added using a dropping funnel into a solution of butyric
anhydride (31.6 g, 0.2 mol) and toluene (43.3 g) at 30 °C in a 200 mL flask under N flow in a
2
water bath. Furthermore, the reaction mixture was stirred at 30 °C for 2 h. A sample of the
solution was analyzed by GC. The yield was calculated relative to the amount of
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ꢀchloroꢀ2ꢀ(trifluoromethyl)benzene.
Distillation (General Procedure)
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wt% aqueous HCl solution (39.2 g) was added dropwise into the reaction mixture.
Furthermore, the solution was stirred for 1 h then left undisturbed to separate oil and water
layers. The oil layer was removed and washed with a 0.015 wt% NaCl aqueous solution (18.6 g)
twice. The oil was distilled under reduced pressure and the main fraction was collected at a
temperature range of 85–89 °C at 1333 Pa.
1
2′ꢀTrifluoromethyl propiophenone 4a: H NMR δ 7.37–7.73 (m, 4H), 2.83–2.90 (q, J = 8 Hz,
19
2H), 1.18–1.24(t, J = 8 Hz, 3H); F NMR δ ꢀ59.29 (s).
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2′ꢀTrifluoromethyl acetophenone 3a: H NMR δ 7.44–7.74 (m, 4H), 2.57–2.60 (s, 3H);
F
NMR δ ꢀ59.35 (s).
ACKNOWLEDGMENT
The authors would like to thank Enago (www.enago.jp) for the English language review.
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