Copper-mediated perfluoroalkylation of heteroaryl bromides with (phen)CuRF

Article abstract of DOI:10.1021/ol500422t

The attachment of perfluoroalkyl groups onto organic compounds has been a major synthetic goal over the past several decades. Previously, our group reported phenanthroline-ligated perfluoroalkyl copper reagents, (phen)CuR _F, which react with aryl iodides and aryl boronates to form the corresponding benzotrifluorides. Herein the perfluoroalkylation of a series of heteroaryl bromides with (phen)CuCF₃ and (phen)CuCF ₂CF₃ is reported. The mild reaction conditions allow the process to tolerate many common functional groups. Perfluoroethylation with (phen)CuCF₂CF₃ occurs in somewhat higher yields than trifluoromethylation with (phen)CuCF₃, creating a method to generate fluoroalkyl heteroarenes that are less accessible from trifluoroacetic acid derivatives.

Full text of DOI:10.1021/ol500422t

Letter
pubs.acs.org/OrgLett
Copper-Mediated Perfluoroalkylation of Heteroaryl Bromides with
(phen)CuRF
Michael G. Mormino, Patrick S. Fier, and John F. Hartwig*
University of California, Department of Chemistry, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: The attachment of perfluoroalkyl groups onto organic
compounds has been a major synthetic goal over the past several
decades. Previously, our group reported phenanthroline-ligated
perfluoroalkyl copper reagents, (phen)CuRF, which react with aryl
iodides and aryl boronates to form the corresponding benzo-
trifluorides. Herein the perfluoroalkylation of a series of heteroaryl
bromides with (phen)CuCF3 and (phen)CuCF2CF3 is reported. The
mild reaction conditions allow the process to tolerate many common
functional groups. Perfluoroethylation with (phen)CuCF2CF3 occurs in somewhat higher yields than trifluoromethylation with
(phen)CuCF3, creating a method to generate fluoroalkyl heteroarenes that are less accessible from trifluoroacetic acid derivatives.
he trifluoromethyl group is present in numerous
Tpharmaceuticals, agrochemicals, and materials. As a result,
there has been considerable interest in developing practical
reactions to incorporate perfluoroalkyl groups into organic
compounds under mild conditions. In medicinal and agro-
chemistry, the introduction of a trifluoromethyl group can lead
to increases in activity and stability.1 The top selling drugs
fluoxetine (Prozac) and mefloquine (Lariam) and the leading
agrochemical fluazinam contain CF3 groups (Figure 1).
electron-withdrawing groups. A single report for the trifluoro-
methylation of aryl chlorides with Pd has been reported.3
However, these reactions require an expensive palladium
precatalyst, ligand, and CF3 source. Most relevant to our
current work, the majority of the current methods have not
been demonstrated to be applicable to the synthesis of
fluoroalkyl heteroarenes with significant scope. This limitation
is important because of the prevalence of heteroarenes in
medicinal and agrochemistry.
The difference in availability of aryl iodides and bromides is
even greater for heteroaryl halides. There are only about one-
fifth as many commercially available iodopyridines compared to
bromopyridines, and the price of 2-iodopyridine is nearly 40
times higher than that of 2-bromopyridine per mole.4 A Reaxys
search shows that there are also twice as many procedures to
synthesize any bromopyridine isomer compared to procedures
to synthesize the corresponding iodopyridines.
Grushin has recently reported the perfluoroalkylation of
heteroaryl bromides with CuCF3 formed by the direct
cupration of HCF3.5a,b Although the functional group tolerance
and yields of this method are high, the CuCF3 reagent cannot
be stored.5c Thus, each reaction must be initiated by generation
of CuCF3 from gaseous HCF3, and such a transformation is
challenging to conduct in common laboratory settings.
Methods for the radical trifluoromethylation of heteroarenes
have also been reported recently.6 While these methods do not
require prefunctionalized substrates, the yields and regioselec-
tivities of these reactions are often modest, and limited
functional group compatibility has been demonstrated. Thus,
methods for the synthesis of fluoroalkylheteroarenes from
heteroaryl bromides with easily handled reagents that occur
with broad scope and complete site selectivity are desirable.
Figure 1. Bioactive compounds containing CF3 groups.
The Swarts reaction, which involves the treatment of
benzotrichlorides with HF or SbF5, remains the most prevalent
method for the industrial-scale synthesis of trifluoromethyl
arenes and certain heteroarenes.2a Although this method is
effective in the bulk production of simple benzotrifluorides, its
utility on the laboratory scale for the synthesis of complex
molecules and late-stage functionalization is limited by the low
functional group compatibility and toxic reagents. Furthermore,
the Swarts reaction cannot be applied to the synthesis of
longer-chain perfluoroalkyl moieties, such as the C2F5 group.
Although there has been considerable progress in copper-
mediated perfluoroalkylation reactions in recent years, these
reactions are mostly limited to aryl iodide and arylboron
substrates.2 Perfluoroalkylation reactions of aryl bromides,
which are more commercially and synthetically available than
aryl iodides, have been limited to substrates containing
Received: February 10, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Letter
Our group recently reported the trifluoromethylation of aryl
iodides with a phenanthroline−CuCF3 complex, (phen)CuCF3
(1) (Figure 2B).7a This thermally stable, commercially available
solid reacts with a variety of aryl iodides and electron-deficient
aryl bromides under mild conditions. We also showed that aryl
bromides can be converted to trifluoromethylarenes indirectly
by initial conversion to arylboronate esters, followed by a
reaction of the boronate with 1 in air.7b
tative bromopyridine containing a potentially reactive ester.
Although the 2-position is activated, the prior methods
reported for trifluoromethylation generate the 2-trifluoro-
methylpyridine in low to modest yield. In contrast, the reaction
of this bromopyridine with 1 occurs in essentially quantitative
yield.
Scheme 1. Trifluoromethylation of Bromopyridines with
a
(phen)CuCF3 (1)
Figure 2. Synthesis of perfluoroalkyl heteroarenes.
Because 1 was shown to react with electron-deficient aryl
bromides, we considered that 1 would react similarly with
heteroaryl bromides that are inherently more electron-deficient
than the corresponding arenes, such as pyridines and diazines.
However, reactions of CuCF3 reagents with bromopyridines
could be challenging because pyridines can bind to the metal
center and alter the inherent reactivity. Moreover, bromopyr-
idines are less reactive toward oxidative addition than
iodopyridines, and the oxidative addition step is likely the
rate-limiting step for reactions with copper centers containing
electron-withdrawing perfluoroalkyl groups.9 We hypothesized
that the chelating phen ligand in preformed 1 would minimize
bonding of the pyridine to the copper center, in addition to
rendering the copper complex isolable and easy to handle.
Herein, we report that copper complexes 1 and 2 react with a
range of heteroaryl bromides to form perfluoroalkylhetero-
arenes in good yields. The reactivity and functional group
compatibility for the reaction of bromopyridines with 1 is
higher than those of prior methods for the fluoroalkylation of
heteroarenes.
a
Reaction conditions: bromopyridine (3, 0.10 mmol) and 1 (0.12
Table 1 shows a comparison of the yield for the
trifluoromethylation of methyl 6-bromopicolinate, a represen-
mmol) in DMF (1 mL) at 80 or 100 °C for 8 h. Yields were
determined by 19F NMR spectroscopy. Yields in parentheses are
b
c
isolated yields. Yield of bis-trifluoromethylated product. Reaction
d
e
was run at 100 °C. 1.5 equiv of 1 was used. Isolated product
Table 1. Comparison of Copper-Mediated
a
contains trace (2−3%) perfluoroethyl product.
Trifluoromethylations of a Functionalized Bromopyridine
The scope of the trifluoromethylation reaction of various 2-,
3-, and 4-bromopyridines with complex 1 is shown in Scheme
1. 2-Bromopyridines containing both electron-donating and
electron-withdrawing substituents at each position of the ring
afforded the products in excellent yields within 8 h. Substrates
bearing aldehyde, ketone, ester, and the Weinreb amide
functionality (3f−k) reacted in good yields; side products
resulting from nucleophilic addition of CF3 to the carbonyl
group were not observed. Competitive addition to a carbonyl
group is commonly observed in systems involving nucleophilic
CF3 reagents.8 In addition, substrates containing nitro and
cyano groups (4e and 4l) reacted in high yields. Ortho-
substituted 2-bromopyridines formed products 4b, 4f, 4g, and
conditions
yield
96%
(phen)CuCF3, DMF, 80 °C
b
t
(PPh3)3CuCF3 (1.0 equiv), Bu-bpy, PhMe, 80 °C
K[(MeO)3BCF3], CuI (20 mol %), phen (20 mol %), DMSO, 60 °C 17%
TESCF3, KF, CuI (10 mol %), phen (10 mol %), DMF/NMP, 60 °C 20%
MeO2CCF3, CsF, CuI (10 mol %), DMF, 160 °C
TESCF3, KF, CuI (1.5 equiv), DMF/NMP, 80 °C
56%
c
d
e
f
24%
<5%
a
b
Yields were determined by 19F NMR spectroscopy. Reference 8a.
c
d
e
f
Reference 8b. Reference 8c. Reference 8d. Reference 8e.
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Letter
4p in 74−94% yield. Protic X−H bonds of alcohols, amides,
and carbamates were tolerated under the reaction conditions.
However, a lower yield (4m, 40%) was observed from the
reaction of a substrate containing a secondary amide compared
to that from a substrate containing a tertiary amide (4n, 92%).
For certain compounds (4m−o), the isolated product was
found to contain trace (2−3%) perfluoroethyl product resulting
from difluorocarbene insertion into the CuCF3 reagent.5c The
reaction of 2,5-dibromopyridine (3d) occurred preferentially at
the 2-position over the 5-position, but the product from
trifluoromethylation at both the 2- and 5-position formed in
15% yield. No product was observed corresponding to
trifluoromethylation at the 5-position alone. 2-Chloropyridines
and pyrimidines were also investigated for their reactivity
toward 1. However, low yields (5−20%) of the trifluoro-
methylated products were obtained from the heteroaryl
chlorides.
Scheme 2. Trifluoromethylation of Heteroaryl Bromides
with (phen)CuCF3 (1)
a
Pyridines containing bromine at the 4-position were less
reactive than those containing bromine at the 2-position. High
yields were observed when the bromoheteroarene contained
electron-withdrawing groups (3ac−ae). The product of
trifluoromethylation was obtained in modest yield from 4-
bromopyridines bearing electron-donating groups (4aa, 4ab).
3-Bromopyridines were less reactive toward this process than
2- and 4-bromopyridines, but synthetically useful amounts of
the 3-trifluoromethylpyridines did form. We presume the lower
reactivity is due to the greater electron density at the 3-position
of pyridines than at the 2- and 4-positions, making them more
akin to bromoarenes and less prone to undergo oxidative
addition to the Cu(I) reagent. Consistent with this assertion,
the reactions of 3-bromopyridines required heating at a higher
temperature (100 °C) than the reactions with 2-bromo-
pyridines (80 °C). The trifluoromethylation of 3-bromo-
pyridines containing electron-donating substituents (3x, 3y)
afforded products in modest yields. However, the trifluoro-
methylation of 3-bromopyridines containing electron-with-
drawing substituents (3s−w) formed the products in good
yields. Thus, this simple reaction provides a method to form a
range of 3-trifluoromethylpyridine derivatives.
To enhance the reactivity of 3-bromopyridines toward 1, we
tested several changes to the reaction conditions (see Table S1
in the Supporting Information). However, changes to the
temperature, equivalents of 1, reaction time, concentration,
ligand, and solvent had little effect on the yield. Catalytic
quantities of Lewis acids to bind to pyridine and decrease
electron density at the 3-position led to no reaction. Reactions
of the corresponding pyridine-N-oxide and N-(TBS)pyridinium
triflate formed the trifluoromethylpyridine derivatives in trace
quantities. We are continuing to investigate methods to
increase the reactivity of electron-rich 3-bromopyridines toward
1.
a
Reaction conditions: bromoheteroarene (5, 0.10 mmol) and 1 (0.12
mmol) in DMF (1 mL) at 80 or 100 °C for 8 h. Yields were
determined by 19F NMR spectroscopy. Yields in parentheses are
b
c
isolated yields. Yield of bis-trifluoromethylated product. Reaction
was run at 100 °C. 1.5 equiv of 1 was used. Isolated product
contains 20% perfluoroethyl product. Isolated on a 4.8 mmol scale.
d
e
f
The electron-rich property of five-membered heterocycles
might lead one to expect that these systems would not react
readily with 1. However, complex 1 does react with certain five-
membered heterocycles containing bromine in the 2-position.
The reactions of 1 with 2-bromo indole (5j), benzimidazole
(5l), and benzoxazole (5k) formed the trifluoromethylated
products in good to high yield. Brominated caffeine was also
transformed to the trifluoromethylated product and isolated on
gram scale in high yield (6m), demonstrating the applicability
of this method for the large-scale trifluoromethylation of
complex heterocyclic substrates. Finally, the nucleoside
derivative 5n underwent trifluoromethylation in high yield.
Reactions of 2-bromofurans and 2-bromothiophenes also were
explored, but only low yields of the trifluoromethylation
product were obtained. Furthermore, unprotected N−H
derivatives of 5i and 5l did not react with 1 to form
trifluoromethylated products.
The scope of the trifluoromethylation reaction with 1
encompassed reactions with other brominated nitrogen hetero-
cycles (Scheme 2). For example, 2- and 5-bromopyrimidines
reacted with 1 to form the corresponding trifluoromethyl-
pyrimidines in good yield (6a−c). Complex 1 also reacted with
a range of bromopyrazines (5d), quinolines (5e, 5f),
quinoxolines (5g), isoquinolines (5h), and aza-indoles (5i)
when bromine was located adjacent to nitrogen. The reaction
with 2,4-dibromoquinoline occurred selectively at the 2-
position; only 18% of the bis-trifluoromethylated side product
(6e) formed.
Given the limited synthetic procedures for the incorporation
of longer chain perfluoroalkyl groups, we investigated the
extension of this reaction to the perfluoroethylation of
bromoheteroarenes with (phen)CuCF2CF3 (2) (Scheme 3).
In fact, the perfluoroethyl heteroarene products were generated
in higher yield than the trifluoromethyl analogues. This higher
yield was observed for 2-, 3-, and 4-bromopyridines. For
example, 3-bromopyridine reacted with 2 to form 3-penta-
fluoroethylpyridine in 74% yield, and 2-methoxy-3-bromo-
pyridine reacted with 2 to form the −C2F5 product in 65%
yield. We propose the increased yields with 2 result, in part,
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Organic Letters
Letter
derivatives of a wide range of heteroarenes as part of studies on
structure−reactivity relationships.
Scheme 3. Perfluoroethylation of Heteroaryl Bromides with
(phen)CuCF2CF3 (2)
a
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, details on reaction development, and
characterization of reaction products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jhartwig@berkeley.edu.
Notes
The authors declare the following competing financial
interest(s): A provisional patent application has been filed by
the University of California. J.F.H. is a founder of Catylix; he
and the company may benefit financially from the expected
results of the PHS-funded research conducted in his laboratory.
ACKNOWLEDGMENTS
■
We thank the NIH (GM-58108) for support of this work and
Catylix for a supply of TMS−C2F5. We thank the NSF and
Chevron for graduate fellowships to M.G.M. and P.S.F.,
respectively.
REFERENCES
■
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a
Reaction conditions: bromoheteroarene (5, 0.10 mmol) and 2 (0.12
mmol) in DMF (1 mL) at 80 or 100 °C for 8 h. Yields were
determined by 19F NMR spectroscopy. Yields in parentheses are
b
c
́ ́
A.; Novikov, M. A.; Martin, E.; Escudero-Adan, E. C.; Novak, P.;
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isolated yields. Yield of bis-perfluoroethylated product. Reaction
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product contains 4% bis-perfluoroethylated product.
d
e
(6) For examples of radical trifluoromethylation reactions, see: (a) Ji,
Y.; Bruecki, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
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from the greater thermal stability of 2 compared to that of 1.
Heating complexes 1 and 2 separately in DMF at 80 °C caused
80% of 1 to decompose, compared to only 6% of 2 after 24 h.
The reactions of bromopyridines with 2 occurred with
similar functional group compatibility as was observed for the
reactions of 1 (Scheme 3). Although the yields were high in
almost all cases, bromopyridines bearing electron-withdrawing
substituents generally reacted in higher yields than those
bearing electron-donating substituents. Various diazines also
underwent the perfluoroethylation reaction.
́
(8) (a) Tomashenko, O. A.; Escudero-Adan, E. C.; Belmonte, M. M.;
Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655. (b) Knauber, T.;
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In summary, we developed a simple synthetic procedure for
the generation of perfluoroalkyl heteroarenes from reactions of
stable CuCF3 and CuC2F5 complexes 1 and 2 with heteroaryl
bromides. These reactions are an improvement over current
perfluoroalkylation reactions of heteroaryl iodides because
heteroaryl bromides are significantly less expensive and more
readily available than heteroaryl iodides. The high reactivity of
complexes 1 and 2, as well as the mild reaction conditions,
allowed for the perfluoroalkylation of heteroaryl bromides
containing both electron-donating and -withdrawing groups as
well as electrophilic and protic functional groups. We anticipate
that this process will enable the synthesis of perfluoroalkyl
(9) Kieltsch, I.; Dubinina, G. G.; Hamacher, C.; Kaiser, A.; Torres-
Nieto, J.; Hutchison, J. M.; Klein, A.; Budnikova, Y.; Vicic, D. A.
Organometallics 2010, 29, 1451.
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