Transition-metal-free synthesis of fluorinated arenes from perfluorinated arenes coupled with grignard reagents

Article abstract of DOI:10.1021/om4011609

A simple method to obtain organofluorine compounds from perfluorinated arenes coupled with Grignard reagents in the absence of a transition-metal catalyst was reported. In particular, the perfluorinated arenes could react not only with aryl Grignard reagents but also with alkyl Grignard reagents in moderate to good yields.

Full text of DOI:10.1021/om4011609

Note
pubs.acs.org/Organometallics
Transition-Metal-Free Synthesis of Fluorinated Arenes from
Perfluorinated Arenes Coupled with Grignard Reagents
Yunqiang Sun, Hongjian Sun, Jiong Jia, Aiqin Du, and Xiaoyan Li*
School of Chemistry and Chemical Engineering, Key Laboratory of Special Functional Aggregated Materials, Ministry of Education,
Shandong University, Shanda Nanlu 27, 250199 Jinan, People’s Republic of China
S
* Supporting Information
ABSTRACT: A simple method to obtain organofluorine compounds from perfluorinated
arenes coupled with Grignard reagents in the absence of a transition-metal catalyst was
reported. In particular, the perfluorinated arenes could react not only with aryl Grignard
reagents but also with alkyl Grignard reagents in moderate to good yields.
rganofluorine compounds are rare in nature but play
RESULTS AND DISCUSSION
■
1
Osignificant roles in many fields such as material science,
The reaction was found while screening the reaction conditions
of perfluorinated arenes with Grignard reagents in the presence
of transition-metal catalysts. At the beginning, we also wanted
to explore a new catalytic system for the nucleophilic
substitution of perfluorinated arenes with Grignard reagents.
However, we found that the yield of the product, 4-
phenyltetrafluoropyridine, was only 10% when pentafluoropyr-
idine reacted with phenylmagnesium bromide in the presence
of [Ni2(iPr2Im)4(COD)] (1).10 A large amount of homocou-
pling product (biphenyl) of phenylmagnesium bromide was
confirmed according to GC-MS analysis. This might be
understood from the work on the mechanism of nickel-
catalyzed coupling of aryl halides by Kochi.11 This result was in
conformity with Radius’s experiment.10 However, when nickel
complex 1 was taken out of the reaction mixture under the
same conditions (as a control experiment), up to a 97% yield of
4-phenyltetrafluoropyridine could be achieved and the yield of
biphenyl was very low (Table 1).
pesticides,2 fluoro-liquid crystals,3 and pharmaceuticals.4 The
existence of one or more fluorine atoms in a drug molecule
might have some decisive effects in changing its biological and
chemical properties. Nucleophilic substitution (SNAr)5 and
transition-metal-catalyzed coupling reactions6 represent two
main strategies for the synthesis of organofluorine compounds,
and significant efforts have been made in these two fields.
However, they suffer some drawbacks. For SNAr reactions, a
complicated reaction system is needed and the yield and
selectivity are not satisfactory. For metal-catalyzed reactions, in
some cases, harsh conditions are required. In addition, metal
catalysts may contaminate products and bring adverse effects to
health and the environment.
Actually, the direct reaction of fluorinated arenes with
organometallic nucleophilic reagents in the absence of
transition metal catalysts can be traced back to the 1960s.7 In
most cases organolithium reagents were used. However, due to
their high reactivity, the selectivity of these reactions was poor.
Di- and/or trisubstituted products were detected. Grignard
reagents were also selected as nucleophilic reagents for the
reaction with perfluorinated arenes,8 but the yield was low.
Since then, for a long time, researchers focused on finding new
catalytic systems to synthesize fluorinated arenes and neglected
this simple but powerful nucleophilic substitution reaction. This
direct method may promote the development of more efficient
pathways to obtain fluorinated arenes. Recently, Matsubara
reported the cleavage of unactivated C−F bonds and
nucleophilic substitution with magnesium reagents and without
using a transition-metal catalyst.9 However, the majority of
those reactions occurred at higher temperatures and the yields
were not satisfactory.
Encouraged by this result, we expanded the substrate scope
of perfluorinated arenes and Grignard reagents. First, we carried
out the substitution reactions of perfluorinated arenes with aryl
Grignard reagents. Moderate to satisfactory isolated yields were
obtained (Scheme 1). From these results it could be concluded
Table 1. Nucleophilic Substitution of Pentafluoropyridine
and Phenylmagnesium Bromide with or without Metal
Catalyst
a
entry
catalyst
yield (%)
1
2
[Ni2(iPr2Im)4(COD)]
10
97
In this paper, we describe a simple method to synthesize
organofluorine compounds by the reaction of perfluorinated
arenes with Grignard reagents and without a transition-metal
catalyst under mild conditions. It should be especially noted
that the perfluorinated arenes could react with not only aryl but
also alkyl Grignard reagents in good yields.
none
a
Yields of isolated products.
Received: November 28, 2013
Published: February 11, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/om4011609 | Organometallics 2014, 33, 1079−1081

Organometallics
Note
Scheme 1. Nucleophilic Substitution of Perfluorinated
Scheme 2. Nucleophilic Substitution Reaction of
Perfluorinated Arenes and Alkyl Grignard Reagents without
Metal Catalyst
Arenes and Aryl Grignard Reagents without Metal
a b
,
a b
,
Catalyst
a
Conditions: perfluorinated arene (1.0 mmol), Grignard reagent (1.5
b
mmol), THF (2 mL), room temperature, 24 h. Yields of the isolated
c
d
products are given in parentheses. 60 °C. Yields based on the in situ
19F NMR.
a
Conditions: perfluorinated arene (1.0 mmol), Grignard reagent (1.5
b
mmol), THF (2 mL), room temperature, 24 h. Yields of the isolated
products are given in parentheses. 60 °C.
c
The substitution reaction of perfluorinated arenes with
Grignard reagents in the absence of a transition-metal catalyst
might proceed via a four-membered-ring transition state similar
to the case in Matsubara’s report.9 The C−F bond cleavage and
C−C bond formation occur simultaneously.
that p-methoxyphenylmagnesium bromide was superior to both
phenylmagnesium bromide and p-methylphenylmagnesium
bromide in most cases when the substituted phenyl Grignard
reagents were employed in the substitution reactions.
Furthermore, 2-thienylmagnesium bromide gave the corre-
sponding substitution products in good yields. In all cases, the
selectivities are very good. Only monosubstituted products
were detected. The replacement of fluorine atoms occurred at
the para position of the −N, −CF3, or −C6F5 group and the β-
position of octafluoronaphthalene.
Subsequently, we explored the nucleophilic substitution
reactions of perfluorinated arenes with alkyl Grignard reagents.
The related results are shown in Scheme 2. Ethyl, n-butyl,
isopentyl, n-octyl, and phenylethyl Grignard reagents were used
in the substitution reactions with perfluorinated arenes. All of
the corresponding organofluorine compounds were obtained in
moderate to good yields. Only monosubstitution occurred with
excellent selectivity at the position of alkylation. It should be
especially noted that some products could not be successfully
isolated because of the low boiling points and volatile
properties. They were confirmed by in situ 19F NMR
spectroscopy and GC-MS. It should also be noted that this
reaction did not occur with hexafluorobenzene as raw material
at room temperature, but the substitution products from
hexafluorobenzene could be obtained at 60 °C in high yields
and with good selectivities (Schemes 1 and 2).
In comparison with the results by Harper,8 we found the
reaction selectivities and yields were improved under our
experimental conditions. Some of Harper’s experiments were
carried out at higher temperatures, while most of the reactions
in this work proceeded at room temperature except for
hexafluorobenzene as starting material (at 60 °C). It was also
found that an increase in temperature is not an appropriate way
to improve the yield. In contrast, higher temperatures reduce
the yields of the expected products, because higher temper-
atures favor the formation of the homocoupling byproducts of
Grignard reagents. In other words, higher temperatures will
reduce the selectivity of the reaction. In addition, it was also
found that pentafluorobenzene could not participate in this
nucleophilic substitution because of its low reactivity.
CONCLUSION
■
In summary, a simple method to obtain organofluorine
compounds from perfluorinated arenes coupled with Grignard
reagents in the absence of a transition-metal catalyst at room
temperature was reported except for the case of hexafluor-
obenzene (at 60 °C). In particular, the perfluorinated arenes
could react with not only aryl but also alkyl Grignard reagents
in moderate to good yields.
1080
dx.doi.org/10.1021/om4011609 | Organometallics 2014, 33, 1079−1081

Organometallics
Note
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C.; Cao, L.; Yin, X.; Xu, H.; Zhang, B. J. Fluorine Chem. 2013, 156, 51.
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EXPERIMENTAL SECTION
■
All reactions were carried out under nitrogen with dry solvents under
anhydrous conditions. [Ni2(iPr2Im)4(COD)] was prepared according
to the reported procedure.10 C5F5N, C7F8, C6F6, C12F10, and C10F8
were obtained from ABCR. The Grignard reagents were prepared
from the corresponding bromide and magnesium turnings in
anhydrous tetrahydrofuran (THF) according to known procedures12
and were titrated prior to use. All other chemicals were used as
purchased. NMR spectra were obtained on a Bruker Avance 300
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1
spectrometer (300 MHz for H NMR; 75 MHz for 13C NMR; 282
MHz for 19F NMR).
Typical Procedure for Nucleophilic Substitution Reactions
between Pentafluoropyridine and Phenylmagnesium Bromide
Catalyzed by [Ni2(iPr2Im)4(COD)] (1). Under an N2 atmosphere
nickel complex 1 (10.5 mg, 0.02 mmol) was dissolved in 1 mL of
THF. Pentafluoropyridine (166 mg, 1 mmol) and phenylmagnesium
bromide (1.5 mmol, 1.2 mL/1.3 M in THF) were added. The reaction
mixture was stirred for 24 h at room temperature and was quenched by
100 mL of H2O. The product was extracted three times with 150 mL
of Et2O. The organic layers were combined and dried over Na2SO4. All
volatiles were removed under reduced pressure. The crude product
was purified by column chromatography over silica gel with petroleum
ether as eluent to provide the corresponding product.
Typical Procedure for Nucleophilic Substitution Reactions
between Perfluorinated Arenes and Grignard Reagents
without Nickel Catalyst. Under an N2 atmosphere the perfluori-
nated arene (1 mmol) was dissolved in 1 mL of THF. Grignard
reagent (1.5 mmol) was added to this solution. The mixture was
stirred until the completion of the reaction. The reaction was
quenched with 100 mL of H2O, and the product was extracted three
times with 150 mL of Et2O. The organic layers were combined and
dried over Na2SO4. All volatiles were removed under reduced pressure.
The crude product was purified by column chromatography over silica
gel with petroleum ether as eluent to provide the corresponding
product.
ASSOCIATED CONTENT
■
S
* Supporting Information
Text and figures giving experimental details and NMR spectra
of fluorinated arenes. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for X.L.: xli63@sdu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support by NSF of China (No.
21172132).
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