A general strategy for the perfluoroalkylation of arenes and arylbromides by using arylboronate esters and [(phen)CuRF]

Article abstract of DOI:10.1002/anie.201106668

A versatile method for the synthesis of aryl perfluoroalkanes from arenes and aryl bromides is described. Substituted arenes or aryl bromides are converted in situ to an aryl boronate ester that readily undergoes perfluoroalkylation in air with [(phen)CuR^F]. A broad range of aryl bromide substrates were perfluoroalkylated in good yield for the first time. [(phen)CuCF₃] is now commercially available and has been prepared on 20g scale. Copyright

Full text of DOI:10.1002/anie.201106668

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Angewandte
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DOI: 10.1002/anie.201106668
Trifluoromethylation
A General Strategy for the Perfluoroalkylation of Arenes and
Arylbromides by Using Arylboronate Esters and [(phen)CuRF]**
Nichole D. Litvinas, Patrick S. Fier, and John F. Hartwig*
A large number of existing and candidate pharmaceuticals
contain perfluoroalkyl groups because these moieties can
favorably affect the physical and biological properties of a
compound.[1] Accordingly, the development of methods to
introduce perfluoroalkyl groups into aromatic compounds has
become increasingly important. To introduce the CF3 moiety,
Scheme 1. Copper-mediated trifluoromethylation of arenes and aryl
bromides.
the simplest perfluoroalkyl group, most current industrial
methods rely on the Swarts reaction,[2] wherein benzotri-
chlorides are treated with HF or SbF5 under forcing con-
ditions. While effective for the bulk synthesis of simple
commodity chemicals, the harshness of this reaction signifi-
cantly limits its utility in complex-molecule synthesis, partic-
ularly for late-stage introduction of a trifluoromethyl group
for studies on structure–activity relationships (SAR). Fur-
thermore, this classical route to trifluoromethylarenes does
not provide access to higher-order perfluoroalkylarenes.
In recent years, synthetic methods have been developed
for the preparation of perfluoroalkyl arenes from aryl
iodides[3] and aryl chlorides.[4] However, analogous methods
to prepare these compounds from aryl bromides, which are
particularly desirable starting materials, due to their ease of
synthesis and wide commercial availability, are notably
lacking. Similarly, methods to prepare perfluoroalkyl arenes
directly from arenes would be valuable because the halogen-
ation step is avoided altogether. Existing catalytic per-
fluoroalkylations of arenes require a directing group or
occur with low selectivity,[5] and no methods currently exist
for the perfluoroalkylation of bromoarenes with a broad
substrate scope.[6,7] Here, we report a general strategy for
accessing perfluoroalkyl arenes from arenes and aryl bro-
mides without directing groups, high temperatures, or acidic
conditions.
converted to the perfluoroalkylarene by reaction with
[(phen)CuRF] (1) in air.[8] These two sequences are comple-
mentary because bromination of arenes is typically controlled
by the electronic properties of the arene and iridium-
catalyzed borylation is controlled by the steric properties of
the arene.[9]
The coupling of arylboronic acids with electrophilic
sources of CF3 to give benzotrifluorides have been described
recently, but arylboronate esters tend to be much less reactive
than boronic acids.[10] We hypothesized that [(phen)CuCF3]
(1a), a reagent we recently reported,[7] and its higher
perfluoroalkyl congeners (1b, 1c) could convert arylboronate
esters to the corresponding perfluoroalkylarenes under
oxidative Chan–Lam-type conditions. Reactions of this
reagent would circumvent the need for excess quantities (2–
5 equiv) of TMSCF3 (Ruppertꢀs reagent) typically used to
compensate for the decompostion of CF3À. Compound 1 is
simple to use because it is a solid that is commercially
available, stable indefinitely under nitrogen, and sufficiently
stable to oxygen and moisture that it can be weighed in air.
We initiated our studies by examining conditions for the
conversion of 4-fluorophenylboronates to the corresponding
benzotrifluoride (Table 1). After surveying a range of bases,
solvents and oxidants, we found that reactions conducted in
DMF with air as the oxidant in conjunction with one
equivalent of KF to activate the boronate ester occurred in
higher yields than those conducted with other oxidants we
tested. With air and added KF, 77% yield of the desired
benzotrifluoride was formed from the pinacolatoboronate
ester, as determined by 19F NMR spectroscopy (Table 1,
entry 2). Reactions with pre-formed [(phen)CuCF3] occurred
in higher yields than those conducted with the reagent
generated in situ (entries 1 and 2).
Our strategy for the synthesis of perfluoroalkyl arenes
from arenes and aryl bromides, shown in Scheme 1, starts
from the formation of an arylboronate ester in situ, either by
iridium-catalyzed borylation of arenes or palladium-catalyzed
borylation of aryl bromides. The arylboronate ester is then
[*] Dr. N. D. Litvinas, P. S. Fier, Prof. Dr. J. F. Hartwig
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
and
Department of Chemistry, University of Illinois, Urbana-Champaign
Urbana, IL 61801 (USA)
E-mail: jhartwig@berkeley.edu
In addition to studying the trifluoromethylation of
pinacolatoboronate esters, we studied the trifluoromethyla-
tion of a variety of less hindered boronate esters and boronic
acids. Reactions of boronic acids under the standard con-
ditions gave the corresponding trifluoromethylated product,
but the yields were lower than those of the reactions of
pinacolatoboronate esters (Table 1, entry 3). Arylboronic
acids containing electron-withdrawing substituents on the
[**] We thank the NIH for funding (GM-58108 to J.F.H. and
1F32M093540-01 to N.D.L.). Carl Liskey is acknowledged for helpful
discussions. phen=phenanthroline; RF =perfluoroalkylated
residue
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106668.
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Table 1: Trifluoromethylation of arylboronate esters.
Table 2: Scope of the one-pot borylation/trifluoromethylation sequence
with disubstituted arenes.[a,b,c]
Entry
X[a]
Conditions
Yield
[%][b]
1
2
3
4
5
6
7
8
Bpin
Bpin
CuI, phen, KOtBu, CF3TMS, KF, air
[(phen)CuCF3], KF, air
[(phen)CuCF3], KF, air
[(phen)CuCF3], KF, air
[(phen)CuCF3], KF, air
[(phen)CuCF3], KF, air
[(phen)CuCF3], KF, air
20 mol% [(phen)CuCF3]
1.2 equiv CF3TMS, KF, air
49
77
36
67
16
10
np
42
B(OH)2
Bnpg
Bcat
BMIDA
BF3K
Bpin
[a] pin=pinacolato, npg=neopentylglycolate, cat=catecholato,
MIDA=N-methylimino diacetate, TMS=trimethylsilyl. [b] Reactions
run on a 0.1 mmol scale; yields determined by 19F NMR spectroscopy
with 4-trifluoromethoxyanisole as an internal standard.
aryl group did, however, react in higher yields than those with
a relatively electron-neutral fluorine substituent (see Sup-
porting Information for additional substrates). Although
reactions conducted with catecholboronate esters and tri-
fluoroborate salts did not give benzotrifluoride products in
high yield, reactions of the corresponding neopentylglycol-
boronate ester proceeded in good yield (Table 1, entry 4).
Finally, we briefly examined the reaction of the pinacolato-
boronate ester with Ruppertꢀs reagent in the presence of
[(phen)CuCF3] as a catalyst (entry 8). Some turnover was
observed, but higher yields were observed with [(phen)-
CuCF3] as reagent, and the latter conditions were explored
further.
Based on these conditions that we developed for the
trifluoromethylation of aryl boronate esters, a one-pot
sequence for the generation of benzotrifluorides from
arenes was developed. This sequence consists of Ir-catalyzed
borylation of the arene,[9] followed by removal of the volatile
components and subsequent copper-mediated trifluorome-
thylation with [(phen)CuCF3]. Because the regioselectivity of
the iridium-catalyzed borylation of arenes is controlled by
steric effects, 1,3-disubstituted arenes generate 1,3,5-trisub-
stituted arylboronate esters and symmetric 1,2-disubstituted
arenes give 1,2,4-trisubstiuted arylboronate esters.[9] Despite
the presence of Ir and other by-products from the borylation
process, the trifluoromethylation of the boronate ester
occurred in the same reaction vessel, and good yields of
benzotrifluorides were obtained over the two-step process.
The scope of the trifluoromethylation of arenes is shown
in Table 2. Both yields determined by 19F NMR spectroscopy
and yields of isolated product are reported; due to the
volatility of the perfluoroalkylarene products and their
similar low polarity to some of the side products, isolated
yields tended to be much lower than the chemical yield
determined by 19F NMR spectroscopy. Amines, pyridines, and
esters were tolerated by the reaction conditions. Although
silyl-protected alcohols were tolerated by the conditions of
the Ir-catalyzed borylation, the silicon–oxygen bond was
cleaved during the trifluoromethylation step. Aryl halides
[a] Reactions run on a 0.1 mmol scale to determine 19F NMR yields and
run on a 0.5 mmol scale to obtain yields of isolated products. 19F NMR
yields are listed first followed by yields of isolated products in
parenthesis. [b] Reaction conditions: 0.75 equiv B2pin2, 0.1 mol% [{Ir-
(cod)OMe}2] (cod=cyclooctadiene), 0.2 mol% dtbpy (4,4’-di-tert-butyl-
2,2’-bipyridyl), 0.5m THF, 808C. [c] Yields determined by 19F NMR
spectroscopy with 4-trifluoromethoxyanisole as an internal standard.
Compounds were isolated by chromatography on silica gel, see
Supporting Information for details. [d] 3 mol% [{Ir(cod)OMe}2], 6 mol%
dtbpy.
À
reacted to form benzotrifluorides by cleavage of a C H bond,
not by cleavage of the carbon–halogen bond. Based on the
À
selectivity for Ir-catalyzed C H borylation, symmetric
1,2-substitued arenes formed products containing a trifluoro-
methyl group at the 4-position. The aldehyde function was not
tolerated by the conditions of the borylation step, but was
tolerated by the conditions of the trifluoromethylation step
(see below).
Like the trifluoromethyl moiety, pentafluoroethyl and
heptafluoropropyl moieties are valuable for modulating the
properties of molecules of interest to the pharmaceutical and
agrochemical industries.[1b] However, methods to prepare
perfluoroalkyl arenes are limited because they cannot be
prepared by halogenation of the corresponding alkylar-
ene.[3c,11] Fortunately, perfluoroalkyl analogs of [(phen)-
CuCF3], such as [(phen)CuCF2CF3] and [(phen)-
CuCF2CF2CF3], are easily prepared.[7] These reagents react
with arylboronate esters in a fashion similar to that of
[(phen)CuCF3], giving perfluoroalkyl arenes in good yields.
Table 3 shows the scope of the one-pot sequence of borylation
and perfluoroalkylation. The reaction yields were generally
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Table 3: Scope of the one-pot borylation/perfluoroalkylation sequence
Table 4: Borylation and trifluoromethylation of arylbromides.[a,b,c]
with disubstituted arenes.[a,b,c]
[a] Reactions run on a 0.1 mmol scale to determine 19F NMR yields and
run on a 0.5 mmol scale to obtain yields of isolated products.
[b] Reaction conditions: 0.75 equiv B2pin2, 0.1 mol% [{Ir(cod)OMe}2],
0.2 mol% dtbpy, 0.5m THF, 808C. [c] Yields determined by 19F NMR
spectroscopy with 4-trifluoromethoxyanisole as an internal standard.
Compounds were isolated by chromatography on silica gel, see the
Supporting Information for details. [d] Approximately 5% 1,2-dibromo-
benzene from protodeborylation could not be separated from the desired
product. [e] 3 mol% [{Ir(cod)OMe}2], 6 mol% dtbpy.
[a] Reactions run on a 0.1 mmol scale to determine 19F NMR yields and
run on a 0.5 mmol scale to obtain yields of isolated products. [b] A small
amount of homodimer was inseparable from the desired product.
[c] Yields determined by 19F NMR spectroscopy with 4-trifluoro-
methoxyanisole as an internal standard. Compounds were isolated by
chromatography on silica gel, see the Supporting Information for details.
unaffected by the nature of the [(phen)CuRF] reagent;
sequences that lead to products of trifluoromethylation,
perfluoroethylation and perfluoropropylation occurred in
similar yields with the same arene.
À
The success of our one-pot sequence consisting of C H
borylation and trifluoromethylation prompted us to inves-
tigate the combination of the borylation and trifluoromethy-
lation of aryl bromides. Despite the widespread utility of aryl
bromides as building blocks for the synthesis of complex
arenes, the development of trifluoromethylations of aryl
bromides has been challenging. We anticipated that per-
fluoroalkyl arenes could be accessed from aryl bromides by
first forming the arylboronate ester in situ. We sought to
identify conditions for the borylation of aryl bromides that
would be compatible with the perfluoroalkylation of arylbor-
onate esters.
Several examples of the perfluoroalkylation of aryl
bromides are shown in Table 4. Trifluoromethylarenes, pen-
tafluoroethylarenes, and heptafluoropropylarenes were
formed in good yield from the arylbromide precursor.
Notably, electron-rich arylbromides, which are typically
unreactive in other copper-mediated trifluoromethylation
methods, gave good yields of the corresponding perfluroal-
kylarenes. Electrophilic functionality such as nitriles, esters,
and aldehydes were tolerated. This method allows access to
1,2-, 1,3-, and 1,4-disubstituted arenes, complementing the
selectivity observed for the Ir-catalyzed borylation of arenes
(see above).
In summary, we have developed a versatile method for the
synthesis of perfluoroalkyl arenes from two common classes
of aromatic reactants. Disubstituted or trisubstituted arenes
and a range of aryl bromides are converted regioselectively to
an arylboronate ester in situ, and this ester readily undergoes
perfluoroalkylation under mild conditions with a stable, pre-
formed copper reagent. By this sequence, arenes are selec-
tively functionalized with regioselectivity that contrasts that
of directed arene perfluoroalkylations. In addition, a variety
of aryl bromides are converted to benzotrifluorides for the
After examining several sets of conditions, we found that
those of the palladium-catalyzed borylation of aryl bromides
reported by Ishiyama, Murata, and Miyaura were most
compatible with the subsequent trifluoromethylation.[8d]
Three equivalents of KOAc were required for the borylation
of the aryl bromide to proceed in high conversion. Unfortu-
nately, the excess KOAc caused the trifluoromethylation step
to occur in low yield. However, filtration of the crude reaction
mixture through a small plug of Celite before the trifluoro-
methylation step allowed the formation of the trifluorome-
thylarene to occur in higher yields.
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chromatography on silica gel with pentane or pentane/Et2O mixtures
as the eluent.
first time under mild conditions. The two processes we report
are complementary because the borylation of arenes is
controlled by steric effects and the bromination that forms
the aryl bromide reagent is controlled by electronic effects.
Both methods are based on recently developed copper
reagents that are thermally stable, easily handled solids.
Studies to explore methods based on these reagents are
ongoing.
Received: September 20, 2011
Published online: November 14, 2011
Keywords: copper · fluorine · one-pot methodology ·
.
perfluoroalkylation · trifluoromethylation
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Experimental Section
General procedure for one-pot generation of perfluoroalkyl arenes
À
via Ir-catalyzed C H borylation: In a nitrogen-filled glove box, the
arene (0.500 mmol, 1 equiv) and a stock solution of B2pin2, [{Ir-
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THF (0.5m). The reaction mixture was heated in a sealed vessel at
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[(phen)CuCF2CF3] (218 mg, 0.600 mmol, 1.2 equiv) or [(phen)-
CuCF2CF2CF3] (248 mg, 0.600 mmol, 1.2 equiv), KF (29.1 mg,
0.500 mmol, 1.0 equiv) and DMF (5 mL, 0.1m) were added, and the
vial was sealed with a screw cap fitted with a septum. Outside of the
glove box, air from a balloon was bubbled into the DMF solution for
5–10 min. The balloon was removed, and the vial was placed in a 508C
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to a separatory funnel. The mixture was washed with 4 ꢁ 40 mL of
H2O and 1 ꢁ 25 mL brine, dried with MgSO4, filtered, and concen-
trated under vacuum. The crude product was purified by column
chromatography on silica gel with pentane or pentane/Et2O mixtures
as the eluent.
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General procedure for one-pot generation of perfluoroalkyl
arenes via palladium-catalyzed C Br borylation: In a nitrogen-filled
À
glove box, the aryl bromide (0.500 mmol, 1 equiv), B2pin2 (139 mg,
0.550 mmol, 1.1 equiv), KOAc (147 mg, 1.50 mmol, 3 equiv),
[PdCl2dppf] (12.2 mg, 0.015 mmol, 3 mol%), and 2.5 mL dioxane
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