Sequential direct SNAr reactions of pentafluorobenzenes with azole or indole derivatives

Article abstract of DOI:10.1021/ol5012554

Sequential regioselective N-arylations through high-yielding catalyst-free direct S_NAr reactions of pentafluorobenzene derivatives with azole or indole derivatives are described. The N-arylated derivatives were further functionalized through a

Full text of DOI:10.1021/ol5012554

Letter
pubs.acs.org/OrgLett
Sequential Direct SNAr Reactions of Pentafluorobenzenes with Azole
or Indole Derivatives
Frederik Diness*,† and Mikael Begtrup
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
S
* Supporting Information
ABSTRACT: Sequential regioselective N-arylations through
high-yielding catalyst-free direct SNAr reactions of pentafluor-
obenzene derivatives with azole or indole derivatives are
described. The N-arylated derivatives were further function-
alized through a microwave-assisted cross-coupling reaction via
C−H bond activation or Suzuki conditions. The order of the
reactions could be reversed, proving full orthogonality between
the reactions which led to well-defined fully substituted
benzene derivatives.
omplex N-arylated azole and pyrrole derivatives are
Table 1. Optimization of Direct SNAr Reaction Conditions
C
currently being intensively investigated as these are
materials for organic light emitting diodes (OLED) and organic
electronics in general.1 A promising new group of these are
substituted benzene derivatives bearing four to six azole/pyrrole
moieties, which has been explored for self-assembling, redox
activity, metal chelation, conductivity, convertible conforma-
tion, and optoelectronic properties.2 However, only benzene
derivatives with four to six identical azole or pyrrole moieties
are known from the literature,2 and until now, no facile
methods for selective tailoring of complex derivatives (e.g.,
asymmetric) within this class have been available.3 Recently, we
reported high-yielding catalyst-free N-arylation of azole or
indole derivatives through direct nucleophilic aromatic
substitution (SNAr) of unactivated monofluorobenzene deriv-
atives.4 Similarly, pentafluorobenzene derivatives have also been
explored within this regime. Here we report that these
derivatives under optimized mild reaction conditions undergo
regioselective high-yielding sequential substitutions. Further-
more, it is demonstrated that the direct SNAr reactions are fully
orthogonal to cross-coupling reactions, which may be
conducted in any reaction order.
b
yields
b
pentafluorobenzene
time
(min)
(conversion)
(%)
a
entry
base (equiv)
(equiv)
a
b
c
d
e
f
Na2CO3 (1)
Na2CO3 (2)
NaOH (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (2)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
1
60
60
60
60
60
60
60
15
15
15
6 (6)
1
7 (7)
1
74 (78)
88 (99)
91 (99)
99 (100)
41 (94)
64 (64)
77 (80)
99 (99)
1
1.5
5
g
h
i
1
1
1.5
5
j
a
Conditions for reactions in the table: benzimidazole (0.1 mmol), base
Initially, benzimidazole was reacted with pentafluorobenzene
in DMA using an inorganic base at room temperature (see the
reaction scheme in Table 1).5 The system was to serve as a
model for functionalizing of polybenzimidazole with perfluor-
obenzene derivatives. Application of cesium carbonate or
tribasic potassium phosphate which has been superior for
reacting monofluorobenzene derivatives,4 however, led to very
slow conversion rates. This may be explained by the low degree
of benzimidazole deprotonation by these bases at room
temperature. However, the use of 1 equiv of sodium tert-
butoxide as a stronger and more soluble base gave high
conversion within 15 min and led to fair yields of the
regioselective monosubstituted product 1. A screen of solvents
proved that combined with sodium tert-butoxide, DMF and
DMA worked equally well, whereas THF, acetonitrile, ethyl
(see table), pentafluorobenzene (see table), DMF (1 mL), −10 to 0
b
°C. Evaluated by HPLC (see the Supporting Information).
acetate, and 2-propanol gave rise to slow conversion rates and
major amounts of byproducts.
Further optimization of the reaction conditions (Table 1)
showed that reducing the temperature and using an excess of
pentafluorobenzene almost eliminated byproduct formation. In
the case of sodium carbonate as base (Table 1, entry b), even
an excess did not enhance the slow conversion rates.
Independent of our work, others have recently published
Received: May 1, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5012554 | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
findings that sodium hydroxide is the optimal base for this
reaction when large excesses of pentafluorobenzene and base
are applied under elevated temperatures.5b Our experiments
revealed that a large excess of sodium tert-butoxide led to major
amounts of byproducts (Table 1, entry g). However, when only
1 equiv of pentafluorobenzene and minor exesss of base were
used, the use of sodium tert-butoxide led to a faster conversion
rate than sodium hydroxide (Table 1, entry c) with only minor
byproduct formation. Hence, sodium tert-butoxide was applied
for the final optimizations (Table 1, entries d−j). Under the
optimized conditions, the N-arylated benzimidazole (1) (1-
(2,3,5,6-tetrafluorophenyl)-1H-benzo[d]imidazole) was ob-
tained in 99% yield within 15 min (Table 1, entry j).
Scheme 2. Sequential SNAr Reactions of
Pentafluorobromobenzene
A closer look at the results from all the N-arylations revealed
that the major byproducts were compounds where additional
fluorides had been substituted by the benzimidazole leading to
bis- or tris-substituted phenyl derivatives. However, this
observation leads to the idea that selective sequential fluorine
displacement could be conducted. In order to explore this
concept the corresponding tetrafluorophenyl derivatives of
pyrazole, benzimidazole, indole, and carbazole were synthesized
and isolated in 82−93% yields using only a minor excess of
pentafluorobenzene (Scheme 1). Gratifyingly, it was found that
addition of excess of a second azole nucleophile within 24 h at
room temperature gave the fully substituted products which
could be isolated in excellent yields.
Scheme 1. Sequential SNAr Reactions of Pentafluorobenzene
amounts and shortening of the reaction time to 30 min gave the
pentasubstituted bromobenzene derivative 13 in 75% yields.
Further reaction of 13 lead to the fully substituted 14, which to
our knowledge is the first example of benzene with three
different C−N-bonded azole substituents.
Alternative funtionalization of 1 through C−H activation was
also explored utilizing cross-coupling reactions (Scheme 3).
Cross couplings of fluorobenzene derivatives and aryl halides
through C−H activation have been reported both by palladium
and copper catalysis.7 However, the reported reaction
conditions include reactions times of 12−24 h and a significant
excess of fluorobenzene derivative. Optimization of the reaction
conditions for compound 1 using a sealed vessel reaction and
microwave heating reduced the reaction time to 15 min. Even
reducing the amount of 1 to only 1.1 equiv still gave rise to 15
in 81% yields. The p-bromo products 9 also facilely underwent
microwave-facilitated cross-coupling under Suzuki conditions.8
Analogous pentafluorobromobenzene could be applied in the
N-arylation reaction giving the corresponding 2,3,5,6-tetra-
fluorobromphenyl containing N-aryl products in 71−79% yields
(Scheme 2). The pentafluorobromobenzene derived products
9−11 were, however, more prone to undergo additional
substitutions when 2 equiv of pentafluorobromobenzene were
applied in these reactions. It was also noticed that small
amounts of the debrominated product (1) as well as the 1-
bromo-2,3,4,5-tetrafluorophenyl derivative were formed. This
regioselectivity of para versus ortho substitution is also
observed for reaction with benzotriazole6 and imidazole.5a
Despite the numbers of N-arylated azole derivatives already
reported, compounds 9 and 10 were not previously reported.
The monoazole-substituted products (9−11) smoothly under-
went full substitution under the same conditions as above,
exemplified by elaborating on the benzimidazole derivative 9.
Surprisingly also the bromo substituent was fully displaced after
overnight reaction leading to compound 12. However, reducing
equivalents of nucleophile and base to almost stoichiometric
Scheme 3. Cross Couplings of SNAr Products
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Letter
To further expand the scope, the reversed order of the N-
arylation and the C−C cross coupling reaction was explored.
Pentafluorobenzene smoothly underwent cross-coupling with a
bromobenzene derivative under the same conditions as above.
Reacting the formed 4′-methoxy-2,3,4,5,6-pentafluorobiphenyl
(16) with a range of azole or pyrole derivatives worked well and
gave rise to the para-substituted derivatives (15 and 17−20) in
82−89% yields (Scheme 4). The starting temperatures for these
reactions were raised to 0 °C as compound 16 had reduced
solubility in DMA below this temperature.
were poorly soluble, which may account for the reduced
isolated yields of 22 even though full conversion of 18 was
observed. Similar observations have been reported for per-
substitution of hexafluorobenzene.2 The steps of the additional
substitutions were found to be governed by a complex
combination of steric hindrance, nucleophilicity of the azole,
and the fluorination pattern. Pursuing partial substitutions was,
however, possible for the reaction of 18 with 2 equiv of
carbazole. The reaction was fully regioselective as only the 2,5-
regioisomer (23) was obtained. This observation is consistent
with previous reports which have determined that the C−F
bond in fluorobenzene is activated by additional fluoro
substituents in the ortho- and meta-positions, whereas fluorine
in the para-position adds little if any to the reactivity.9 A similar
substitution pattern is also observed for tetrasubstitution of
hexafluorobenzene with pyrazole.2f
Scheme 4. SNAr Reactions of Biphenyl Derivatives
The easy access to the difluorinated 23 paved the way for
exploration of additional substitution with 2 equiv of a third
nucleophile. Such reaction worked smoothly and is exemplified
here by reaction with 4-methylpyrazole where the expected
product 24 could be obtained in 94% yields.10 By these means a
nonsymmetrical fully substituted benzene derivative with four
different substituents could be obtained with full control of
regioselectivity.
These results demonstrate that pentafluorobenzene deriva-
tives undergo direct SNAr substitution of fluorine with azole/
indole dervatives without major deactivation of the remaining
fluoro substituents. This enables sequential regioselective
subsitution of fluorine atoms with up to three different azole
and/or indole dervatives. Combined with C−C cross couplings,
these catalyst-free N-arylation reactions lead to new multi-
substituted aryl derivatives with potential use within molecular
optoelectronics, material science, and biological applications.
The generated tetrafluorobiphenyl derivatives smoothly
underwent full substitution here exemplified by per-substitution
of compound 15 and 18 with carbazole or pyrazole (Scheme
5). We did not find any limitations in the combination of azole
or indole derivatives within these reactions and as seen for 22
even very sterically congested compounds could be obtained by
this method. However, many of the more lipophilic products
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 5. Sequential SNAr Reactions of Azole−
Tetrafluorobiphenyl Derivatives
S
Detailed experimental procedures, HPLC chromatograms,
NMR spectra and data, and other characterization data of
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fdi@sund.ku.dk.
Present Address
†Center for Evolutionary Chemical Biology, Department of
Chemistry, University of Copenhagen, Universitetsparken 5,
DK-2100 Copenhagen, Denmark.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Danish Strategic Research Foundation of Energy and
Environment is acknowledged for supporting this research
(Grant No. 2104-05-0026).
REFERENCES
■
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