Regioselective radical arylation of anilines with arylhydrazines

Article abstract of DOI:10.1021/jo301980j

Substituted 2-aminobiphenyls have been prepared from arylhydrazines and anilines via radical arylation reactions under simple oxidative conditions. The strong directing effect of the free and unprotonated amino functionality leads to high regioselectivities, and anilines have been shown to be significantly better aryl radical acceptors than nitrobenzenes or phenyl ethers. The methodology is also applicable to phenols, which react best as phenolates under strongly basic conditions. Finally, radical arylation reactions of anilines and anilinium salts under various conditions have for the first time demonstrated that regioselectivity can also be controlled through the rearomatization step and that the addition of an aryl radical to a substituted benzene might even be reversible.

Full text of DOI:10.1021/jo301980j

Article
pubs.acs.org/joc
Regioselective Radical Arylation of Anilines with Arylhydrazines
Hannelore Jasch, Julia Scheumann, and Markus R. Heinrich*
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universitat Erlangen-Nurnberg,
̈
̈
Schuhstraße 19, 91052 Erlangen, Germany
S
* Supporting Information
ABSTRACT: Substituted 2-aminobiphenyls have been prepared
from arylhydrazines and anilines via radical arylation reactions under
simple oxidative conditions. The strong directing effect of the free
and unprotonated amino functionality leads to high regioselectiv-
ities, and anilines have been shown to be significantly better aryl
radical acceptors than nitrobenzenes or phenyl ethers. The
methodology is also applicable to phenols, which react best as
phenolates under strongly basic conditions. Finally, radical arylation
reactions of anilines and anilinium salts under various conditions
have for the first time demonstrated that regioselectivity can also be
controlled through the rearomatization step and that the addition of
an aryl radical to a substituted benzene might even be reversible.
Herein, we now describe arylhydrazines as radical sources for
the selective arylation of anilines.
INTRODUCTION
■
The Gomberg−Bachmann reaction,1 which was first reported
in 1924, is a well-known method for the preparation of biaryls
from aryldiazonium salts by homolytic aromatic substitution.2,3
Attempts to improve this reaction, e.g., by using phase-transfer
conditions,4 could, however, not significantly increase its
attractiveness. The most important reason for this is the
advantage of modern organometallic cross-coupling reactions
regarding regioselectivity.5 Despite the fact that the Gomberg−
Bachmann reaction can formally be classified as C−H
activation6 so that simple and cheap starting materials can be
used, the lack of selectivity limits the scope of suitable
substrates to a few compounds among which simple benzene is
the by far most important.7,8 Because of the comparably slow
addition of aryl radicals to substituted benzenes,9 the aromatic
substrate often needs to be employed in large excess and is
therefore commonly used as solvent. Such limitations even
remain for the recently developed organocatalytic biaryl
syntheses starting from iodobenzenes.10
RESULTS AND DISCUSSION
■
The oxidative degradation of arylhydrazines that leads to aryl
radicals via the intermediate formation of instable diazenes has
been essentially known for a long time.17 Interestingly,
oxidations of arylhydrazines can be carried out under mild
conditions and also at low temperatures, which we felt might be
a key to achieve or improve selectivity.18 In addition to the
desired regioselectivity of the radical arylation, the oxidant
should also preferentially oxidize the hydrazine and not the
aniline. In case the aniline remains susceptible toward the
chosen oxidant, azo compounds can be expected as major side
products from an oxidative dimerization reaction. A number of
oxidants including peroxodisulfate,19a ferrate salts,19b copper
salts,19c hypervalent iodine species,19d manganese dioxide,19e
potassium permanganate,19f and hydrogen peroxide19g,h have
been reported to enable this conversion in high yield.19 The
results of our first study to identify possible oxidants and
reaction conditions are summarized in Table 1.
The fact that selectivity is difficult to achieve in homolytic
aromatic substitutions proceeding via reactive aryl radicals
prompted us to investigate in more detail which substituents on
the aromatic core are suited to control regioselectivity. The first
studies in this field revealed that especially amino groups, as
they are present in anilines, are highly directing substituents.11
In combination with aryldiazonium salts,12 however, special
precautions have to be taken to prevent the conversion of these
substrates to azobenzenes or triazenes.13
Alternative and also well-established sources for aryl radicals
are bromo- and iodoarenes, which can be reacted under a wide
range of reductive conditions.14 Recently, arylboronic acids15
and arylhydrazines16 have gained considerable interest as
reactants in aryl radical reactions under oxidative conditions.
The results in Table 1 show that 4-chlorophenylhydrazine
(1) can be oxidized with sufficient selectivity over 4-
fluoroaniline (2), which is even present in a 20-fold excess.
Among the oxidants, potassium superoxide, potassium
hexacyanoferrate(III), and hydrogen peroxide even showed
perfect selectivity as the azobenzene 4 could not be detected in
the crude product mixture (entries 2, 6, and 7). Since all
reactions were run until complete conversion of the hydrazine20
and no major side products could be determined besides
azobenzene 4 (for entries 1 and 3−5), we assume that
Received: September 18, 2012
Published: November 6, 2012
© 2012 American Chemical Society
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Table 1. Comparison of Oxidants and Reaction Conditions
for the Synthesis of Aminobiphenyl 3 from 4-
Table 2. Synthesis of 2-Aminobiphenyls
Chlorophenylhydrazine (1) and 4-Fluoroaniline (2)
a
b
entry
hydrazine: R1 =
aniline: R2 =
aminobiphenyl (%)
1
2
1: 4-Cl
5: 3,4-Cl
6: 2-Cl
7: 4-CN
8: 4-OMe
1: 4-Cl
9: 4-F
2: F
3 (53)
2: F
16 (62)
17 (56)
3
2: F
b
c
aminobiphenyl 3
azobenzene 4
c
a
4
2: F
18 (58), (46)
entry
oxidant (equiv), conditions
MnO2 (5), CH3CN, rt
(%)
(%)
c
5
2: F
19 (32)
1
2
3
4
5
63
54
59
56
54
11
6
11: Cl
12: Br
12: Br
12: Br
13: CN
14: OMe
15: H
15: H
15: H
20 (47)
21 (45)
KO2 (4), CH3CN, −10 °C
Mn(OAc)3 (3), CH3CN, rt
KMnO4 (3), CH3CN, rt
7
5
32
2
c
8
1: 4-Cl
6: 2-Cl
1: 4-Cl
1: 4-Cl
10: 3,4,5-F
1: 4-Cl
6: 2-Cl
22 (48), (54)
9
23 (57)
NaIO4 (3),
(CH3CN/H2O = 7:1), rt
c
10
11
12
13
14
24 (29), (35)
c
6
7
K3[Fe(CN)6] (3),
55
36
25 (39), (35)
(CH3CN/H2O = 7:1), rt
26 (75, o:p = 59:16)
27 (54, o:p = 41:13)
28 (70, o:p = 49:21)
H2O2 (10), CH3CN, rt
a
Hydrazine 1 (1.00 mmol in 2 mL of CH3CN) was added to the
reaction mixture (5 mL of CH3CN or CH3CN/H2O) over a period of
a
Hydrazines were added to the reaction mixture over a period of 1 h.
1 h. Reactions monitored by TLC and continued until total
Reactions continued until total consumption of the hydrazine (ca. 2 h,
b
1
consumption of 1 (ca. 2 h). Yields determined by H NMR with
dimethyl terephthalate (δ = 8.10 ppm (s, 4 H)) as internal standard.
b
TLC control). Isolated yields. Hydrazine used as free base.
c
Hydrazine used as hydrochloride; NaHCO3 (5 equiv) added to the
c
Yield of azobenzene related to the quantity of aminobiphenyl 3.
reaction mixture.
hydrogen abstraction by the highly reactive chlorophenyl
radicals occurs to a remarkable extent.12 The resulting volatile
chlorobenzene is not found among the products due to a
concentration of reaction mixture in vacuo prior to analysis. A
repetition of the experiment in enty 1 with a careful workup
gave the product 3 and chlorobenzene in 30% yield.
Comparative experiments conducted in CD3CN gave chlor-
obenzene and 4-deuteriochlorobenzene in a ratio of 37:1, which
demonstrates that only a small amount of hydrogen abstraction
originates from the solvent and the major amount from the
NH2 group of 4-fluoroaniline (2) or from the rearomatization
step (Scheme 3).
Because of the simple reaction conditions and easy workup
as well as the ready availability and low cost, manganese dioxide
was chosen as the preferred oxidant. A series of experiments
was conducted to determine scope and limitations of the 2-
aminobiphenyl synthesis (Table 2).
For some of the products, we compared the influence of
replacing the arylhydrazine by its hydrochloride salt accom-
panied by 5 equiv of sodium hydrogen carbonate. Minor
differences in product formation were observed for amino-
biphenyls 22, 24, and 25 (entries 8, 10, and 11). Only
aminobiphenyl 18 (entry 4) was obtained with a remarkably
better yield when starting from hydrazine 7 than from the
corresponding hydrochloride. 4-Methoxyphenylhydrazine (8)
was used as hydrochloride salt due to the low stability of the
corresponding free base.
Regarding the substituents on the arylhydrazine, a signifi-
cantly decreased yield was only found for the 4-methoxy
derivative 8 in the series of reactions with 4-fluoroaniline (2)
(entries 1−5). Changes from halogen substituents on the
aniline (entries 1−9) to an electron-withdrawing group, such as
cyano (entry 10), or an electron-donating group, such as
methoxy (entry 11), also led to lower yields. Not surprisingly, a
comparably large amount of accompanying azobenzene
(25:4,4′-dimethoxyazobenzene = 2:1) was isolated from the
arylation of p-anisidine (14) (entry 11), which represents the
most easily oxidizable substrate in the series of anilines.
Unexpectedly, however, we could not detect or isolate the
regioisomer resulting from the aryl radical attack onto the meta-
position of p-anisidine (14). Previous studies had shown that,
due to the significant radical stabilizing effect of the methoxy
group, p-anisidine (14) can not be reacted regioselectively with
aryl radicals.11c The arylation experiments with aniline (15)
gave a mixture of ortho- and para-isomers with a clear
preference for the ortho-product.21 With an ortho-substituent
on the arylhydrazine, such as in the 2-chloro derivative 6, the
selectivity is, however, decreased from ortho:para = 4:1 (entries
12 and 13) to a ratio of 2.5:1 (entry 14).
Since the optimization experiment with potassium super-
oxide had given aminobiphenyl 3 as pure product without need
for further purification (Table 1), although at a slightly lower
yield than manganese dioxide, we also used the superoxide for
three preparative experiments. Thus, the aminobiphenyls 3, 16,
and 20 were again obtained in high purity and with yields of
39%, 58%, and 37%, respectively.
To get a better insight in the relative reactivity of the newly
investigated anilines, the known aryl radical acceptors
furan,16b,22 phenol,23 and anisole4 were submitted to similar
reactions conditions (Scheme 1).
The yield of the reaction with furan leading to 2-(4-
chlorophenyl)furan (29) is comparable to experiments by
Demir16b with manganese triacetate and hydrazinium chlorides.
Phenol and anisole are obviously less reactive aryl radical
acceptors than anilines since the biphenyl alcohol 30 and
biphenyl ether 31 were obtained in lower yields. The
distribution of isomers of 31 in the arylation of anisole is not
much different from the product patterns found in Gomberg−
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(entry 2) or 4-fluoronitrobenzene (33) (entry 3), the aniline-
derived aminobiphenyl 3 was found as major product with a
ratio of ca. 10:1 to the biphenyls 35 and 36. Although these
results clearly suggest that an amino group renders the benzene
core much more reactive toward a radical attack than nitro or
methoxy groups, as they are present in the competing
substrates 32 and 33, it is difficult to draw a more precise
conclusion due to the fact that the combined yields of 3 and 35,
and 3 and 36, do not amount to the 51% obtained in the
control experiment. A possible reason for this decrease in
overall yield might be that the competing substrates 4-
fluoroanisole (32) and 4-fluoronitrobenzene (33) have been
attacked by the 4-chlorophenyl radical to a comparably larger
extent, but the final yield was lowered due to difficulties in the
rearomatization step (see below) or a somehow low stability of
the products 35 and/or 36 under the given reaction conditions.
A more precise conclusion can be drawn from the
experiment with benzene (34) as competing substrate (Table
3, entry 4), since the aminobiphenyl 3 was obtained in a yield
comparable to the control experiment (Table 3, entry 1) and
the original preparative attempt (Table 2, entry 1). The ratio of
4-fluoroaniline (2)/benzene (34) = 3:1 was chosen to account
for the six equal positions on the benzene core in relation to the
two ortho-positions of the aniline. From the ratio of the
products 3 and 37 (entry 4), we conclude that an ortho-position
of 4-fluoroaniline (2) is at least 15 times more reactive than a
single position on benzene. With this relative rate per (reactive)
position, and based on the known rate constant for the addition
of aryl radicals to benzene (k = 4.5 × 105 M−1 s−1),9 an at least
5-fold value of k = 2.3 × 106 M−1 s−1 can be derived for the
addition of aryl radicals to 4-fluoroaniline (2).27
The results of the oxidative arylation of anilines reported
herein as well as a recent study on a new variant of the
Gomberg−Bachmann arylation11c clearly demonstrate that free
amino functionalities, as they are present in anilines, are highly
activating and directing substituents for the purpose of radical
arylations. Since we have previously also observed a certain
regioselectivity for radical arylations of anilines under acidic
conditions, under which the aniline was definitely protonated
and the directing effect of the free amino group cannot have
been operative, we wondered whether the product distribution
can also be influenced through the rearomatization step.
Generally, there is broad agreement that the key step in all of
these reactions is the addition of an aryl radical to the aromatic
substrate, and that the resulting cyclohexadienyl-type radicals
almost always find a way to rearomatize.10a
Scheme 1. Arylation of Furan, Phenol, and Anisole
Bachmann arylations of anisole.4 Not surprisingly, the reactivity
of phenol could significantly be improved by the addition of
excess sodium hydroxide to the reaction mixture.23 In this way,
more electron-rich phenolate ions act as radical acceptors and
the original aromatic hydroxy group of the phenol can no
longer stabilize the aryl radical through hydrogen atom transfer.
Our initial concern that these two positive aspects might be
counterbalanced by an extensive formation of dimerization
products from the more easily oxidizable phenolate ions,
compared to phenol, did not prove true.24 Related experiments
with 4-fluoroaniline (2) in the presence of stronger bases
(potassium carbonate or sodium hydroxide) showed that
arylation reactions of anilines are independent of base
concentration.25
To directly compare the effect of the free amino functionality
present in anilines on the arylation, and to get a first idea about
relative reaction rates, we conducted a few simple competition
experiments. The control reaction for this series was run with
10 equiv of 4-fluoroaniline (2) (Table 3, entry 1) and showed
that a reduction of the excess of aniline does not lead to
significantly decreased yields (cf. 53%, Table 2, entry 1). When
the arylation was then carried out with a mixture of 4-
fluoroaniline (2) and equal amounts of 4-fluoroanisole (32)
Table 3. Competition Experiments for the Addition of the 4-
Chlorophenyl Radical to Various Substrates
For this mechanistic study, we used 4-methoxyphenylhy-
drazine (8) as an aryl radical source in combination with
ammonium cerium(IV) nitrate. Preliminary experiments had
shown that arylhydrazines react sluggishly with other oxidants
under strongly acidic conditions (including manganese dioxide)
and that nondonor-substituted arylhydrazines are even more
difficult to oxidize. A comparison of two reactions depicted in
Scheme 2 (eqs 1 and 2) then clearly demonstrated that there
remains indeed no directing effect if the amino functionality is
protonated, and aminobiphenyl 19 and its regioisomer 19′ were
observed in almost equal amounts (Scheme 2, eq 2).
For comparison, the arylation of protonated 4-fluoroaniline
(2) under reductive conditions using the 4-methoxyphenyldia-
zonium salt 38 instead of hydrazine 8 as radical source,
proceeded regioselectively and aminobiphenyl 19 was found as
only regioisomer (Scheme 2, eq 3).11a As the reaction above
had shown that the aryl radical attacks both ring positions of 4-
products
entry
competing substrates (equiv)
4-fluoroaniline (2) (10) (control)
(%)
a
a
1
2
3 (51)
3 (35)
4-fluoroaniline (2) (10) vs 4-fluoroanisole (32) (10)
b
b
b
35 (<3)
a
3
4
4-fluoroaniline (2) (10) vs 4-fluoronitrobenzene (33)
(10)
3 (34)
36 (<4)
a
4-fluoroaniline (2) (15) vs benzene (34) (5)
3 (52)
37 (<3)
a
b
1
Isolated yields. Yields of products 35, 36, and 37 derived from H
NMR spectra of the crude reaction mixtures and by comparison with
literature data (ref 26).
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Scheme 2. Regioselectivity under Various Reaction
Conditions
Scheme 3. Regioselectivity under Neutral and Acidic
Conditions
fluoroanilinium ions (Scheme 2, eq 2), the differentiation and
regiocontrol under reductive conditions (Scheme 2, eq 3) must
have occurred in the rearomatization step. For anilines which
do not bear directing substituents in the para-position (e.g., R2
= OH, OMe),11a the present results can be summarized as
depicted in Scheme 3.
Obviously, it is therefore possible to achieve regioselectivity
in the arylation of anilines in two ways, either by running the
reaction under neutral or basic conditions to exploit the
strongly directing effect of the amino functionality or by
applying acidic and reductive conditions that allow rear-
omatization only for cyclohexadienyl intermediate 40. Because
no side products were so far isolated that could give insight into
the fate of the cyclohexadienyl-type radical 41 under acidic
reductive conditions, radical 41 might decompose or even
reversibly evolve back to an aryl radical and a fluoroanilinium
ion. Such reversibility has so far only been reported for the
attack of alkyl radicals to benzenes.28 In general, higher yields
can be expected from the arylation of free anilines. The aryl
radical addition to anilines is certainly several times faster than
to anilinium ions (cf. Table 3), and important side reactions
such as hydrogen abstraction are thus far more effectively
suppressed.
Scheme 4. Synthesis of Xemium (45)
An important application for 2-aminobiphenyls is the
synthesis of fungicides.29 Scheme 4 shows the conversion of
the readily available aminobiphenyl 26 with pyrazolecarboxylic
acid chloride 44 into the recently introduced Xemium (45).30
To date, the aminobiphenyl precursors for fungizides such as
Xemium have been produced by palladium-catalyzed cross-
coupling reactions that rely on more elaborate starting
materials.
functionality allows the reactions to proceed with good
regioselectivity, and anilines were found to be significantly
better aryl radical acceptors than commonly employed
substrates such as nitrobenzenes or phenyl ethers. Furthermore,
radical arylation reactions under strongly oxidizing conditions
showed that regioselectivity can be controlled through the
rearomatization step and that the addition of an aryl radical to a
substituted benzene might even be reversible. From a synthetic
point of view, the methodology is attractive due to the use of
cheap and readily available starting materials. Since it is
especially suited for halogenated arylhydrazines and anilines, it
represents a valuable extension to known palladium-catalyzed
cross-coupling reactions.
SUMMARY
■
In summary, we have described a new synthetic access to 2-
aminobiphenyls31 that is based on the arylation of anilines using
arylhydrazines as radical sources under oxidative conditions.
The directing effect of the free (and unprotonated) amino
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2′-Chloro-5-fluorobiphenyl-2-amine (17). According to GP 2,
the title compound was prepared from 2-chlorophenylhydrazine (6)
(143 mg, 1.00 mmol), 4-fluoroaniline (2) (1.92 mL, 20.0 mmol), and
MnO2 (435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 17 (124 mg, 0.56 mmol, 56%): dark
purple oil; Rf = 0.4 (hexane/EtOAc = 4:1) (UV); 1H NMR (600 MHz,
CDCl3) δ 6.73 (dd, JHF = 4.8 Hz, J = 8.8 Hz, 1 H), 6.81 (dd, J = 3.0
Hz, JHF = 8.9 Hz, 1 H), 6.93 (dt, J = 3.0 Hz, JHF = 8.4 Hz, 1 H), 7.30−
7.36 (m, 3 H), 7.48−7.52 (m, 1 H); 13C NMR (91 MHz, CDCl3) δ
115.7 (d, JCF = 22.2 Hz, CH), 116.7 (d, JCF = 7.8 Hz, CH), 116.8 (d,
JCF = 22.7 Hz, CH), 126.5 (d, JCF = 7.3 Hz, Cq), 127.3 (CH), 129.5
(CH), 130.0 (CH), 131.7 (CH), 133.7 (Cq), 136.8 (d, JCF = 1.6 Hz,
Cq), 139.6 (Cq), 156.1 (d, JCF = 237.2 Hz, Cq); 19F NMR (339 MHz,
CDCl3) δ −129.6; MS (EI) m/z 252 (15), 250 (9), 223 (13) [37Cl-
M+], 221 (39) [35Cl-M+], 187 (13), 186 (100), 185 (64), 184 (13),
157 (9), 92 (13); HRMS (EI) calcd for C12H9ClFN [M+] 221.0407,
found 221.0407.
EXPERIMENTAL SECTION
■
General Experimental Methods. Solvents and reagents were
1
used as received. H NMR spectra were recorded on 360 and 600
MHz spectrometers using CDCl3 as solvent referenced to TMS (0
ppm) or CHCl3 (7.26 ppm). 13C NMR spectra were recorded at 90.6
and 150.9 MHz in CDCl3 using CDCl3 (77.0 ppm) as standard. 19F
NMR spectra were recorded at 338.8 MHz using CFCl3 (0 ppm) or
C6F6 (−164.9 ppm) as standard. Chemical shifts are reported in parts
per million (ppm). Coupling constants are in hertz (J, Hz). The
following abbreviations are used for the description of signals: s
(singlet), bs (broad singlet), d (doublet), dd (double doublet), t
(triplet), q (quadruplet), m (multiplet). Mass spectra were recorded
using a GC mate II GC−MS system with electron-impact ionization
(EI) and a sector field mass analyzer for MS and HRMS
measurements. Analytical TLC was carried out on silica gel plates
using short wave (254 nm) UV light and KMnO4 to visualize
components. Silica gel (Kieselgel 60, 40−63 μm) was used for flash
column chromatography.
General Procedure for the Synthesis of Arylhydrazines (GP
1). To a solution of the aniline (20.0 mmol) in acetic acid (10 mL) at
rt was added concd HCl (50 mL). After cooling to 0 °C, a solution of
NaNO2 (1.38 g, 20.0 mmol) in water (4 mL) was added dropwise and
stirring at 0 °C was continued for 1 h. The cold mixture was filtered,
and a precooled solution of SnCl2 × 2 H2O (10.0 g, 44.3 mmol) in
concd HCl (10 mL) was added dropwise to the filtrate at 0 °C. After 1
h, the formed precipitate was collected by filtration and washed with
saturated aqueous NaCl (30 mL). The hydrazine hydrochloride was
dissolved in diluted aqueous NaOH (2 M, 100 mL) and extracted with
diethyl ether (2 × 100 mL). The combined organic phases were
washed with water and dried over Na2SO4. After removal of the
solvent under reduced pressure, the hydrazine was used without
further purification.32
General Procedure for the Synthesis of Aminobiphenyls
from Arylhydrazines with MnO2 (GP 2). To a stirred suspension of
the aniline derivative (20.0 mmol) and MnO2 (435 mg, 5.00 mmol) in
acetonitrile (5 mL) at rt was added dropwise a solution of the
arylhydrazine (1.00 mmol) in acetonitrile (2 mL) over a period of 1 h.
After completion of the reaction, as monitored by TLC, the reaction
mixture was filtered over Celite. The filter cake was further washed
with ethyl acetate, and the solvents were removed under reduced
pressure. The remaining aniline was recovered by Kugelrohr
distillation, and the products were purified by column chromatography
on silica gel (as described with each product).
General Procedure for the Synthesis of Aminobiphenyls
from Arylhydrazine Hydrochlorides with MnO2 and NaHCO3
(GP 3). To a stirred suspension of the aniline derivative (20.0 mmol),
NaHCO3 (420 mg, 5.00 mmol) and MnO2 (435 mg, 5.00 mmol) in
acetonitrile (5 mL) at rt was added the arylhydrazine hydrochloride
(1.00 mmol) in portions over a period of 10 min. After completion of
the reaction, as monitored by TLC, the reaction mixture was filtered
over Celite. The filter cake was further washed with ethyl acetate. The
organic layer was washed with water (30 mL) and saturated aqueous
NaCl and dried over Na2SO4. The solvent was removed under reduced
pressure. The remaining aniline was recovered by Kugelrohr
distillation, and the products were purified by column chromatography
on silica gel (as described with each product).
4′-Cyano-5-fluorobiphenyl-2-amine (18). According to GP 2,
the title compound was prepared from 4-cyanophenylhydrazine (7)
(133 mg, 1.00 mmol), 4-fluoroaniline (2) (1.92 mL, 20.0 mmol), and
MnO2 (435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 18 (123 mg, 0.58 mmol, 58%): brown
crystalline solid; mp 163−165 °C; Rf = 0.2 (hexane/EtOAc = 4:1)
(UV); 1H NMR (600 MHz, CDCl3) δ 3.68 (bs, 2 H), 6.73 (dd, JHF
=
4.7 Hz, J = 8.7 Hz, 1 H), 6.84 (dd, J = 2.9 Hz, JHF = 9.0 Hz, 1 H), 6.93
(dt, J = 2.9 Hz, J = 8.4 Hz, JHF = 8.4 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2
H), 7.75 (d, J = 8.3 Hz, 2 H); 13C NMR (91 MHz, CDCl3) δ 111.4
(Cq), 116.2 (d, JCF = 18.3 Hz, CH), 116.4 (d, JCF = 18.9 Hz, CH),
117.1 (d, JCF = 7.6 Hz, CH), 118.6 (Cq), 126.3 (d, JCF = 11.3 Hz, Cq),
129.7 (2 × CH), 132.7 (2 × CH), 139.4 (d, JCF = 2.0 Hz, Cq), 143.5
(d, JCF = 1.7 Hz, Cq), 156.4 (d, JCF = 237.4 Hz, Cq); 19F NMR (339
MHz, CDCl3) δ −128.6; MS (EI) m/z 213 (15), 212 (100) [35Cl-M+],
211 (38), 210 (18), 185 (5), 184 (9), 158 (4), 157 (4), 85 (9), 83
(12); HRMS (EI) calcd for C13H9 F N2 [M+] 212.0750, found
212.0750.
5-Fluoro-4′-methoxybiphenyl-2-amine (19). According to GP
3, the title compound was prepared from 4-methoxyphenylhydrazine
hydrochloride (8( × HCl)) (175 mg, 1.00 mmol), 4-fluoroaniline (2)
(1.92 mL, 20.0 mmol), NaHCO3 (420 mg, 5.00 mmol), and MnO2
(435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 19 (69.2 mg, 0.32 mmol, 32%): black
amorphous solid; mp 63−65 °C; Rf = 0.3 (hexane/EtOAc = 4:1)
1
(UV); H NMR (360 MHz, CDCl3) δ 3.85 (s, 3 H), 6.68 (dd, JHF
=
4.9 Hz, J = 9.2 Hz, 1 H), 6.80−6.88 (m, 2 H), 6.98 (d, J = 8.8 Hz, 1
H), 7.36 (d, J = 8.9 Hz, 1 H); 13C NMR (151 MHz, CDCl3) δ 55.3
(CH3), 114.3 (2 × CH), 114.5 (d, JCF = 22.2 Hz, CH), 116.4 (d, JCF
=
7.8 Hz, CH), 116.7 (d, JCF = 22.2 Hz, CH), 128.5 (d, JCF = 7.3 Hz,
Cq), 130.0 (2 × CH), 130.8 (Cq), 139.6 (d, JCF = 2.3 Hz, Cq), 156.4
(d, JCF = 236.2 Hz, Cq), 159.1 (Cq); 19F NMR (339 MHz, CDCl3): δ
−129.6; MS (EI) m/z 218 (15), 217 (100) [M+], 216 (10), 202 (28),
186 (8), 185 (8), 174 (10), 172 (10), 147 (12), 146 (10); HRMS (EI)
calcd for C13H12FNO [M+] 217.0903, found 217.0902.
4′,5-Dichlorobiphenyl-2-amine (20). According to GP 2, the
title compound was prepared from 4-chlorophenylhydrazine (1) (143
mg, 1.00 mmol), 4-chloroaniline (11) (2.55 g, 20.0 mmol), and MnO2
(435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 20 as a brown amorphous solid (112
mg, 0.47 mmol, 47%), mp 77−80 °C. The analytical data obtained are
in agreement with those reported in ref 11a.
5-Bromo-4′-fluorobiphenyl-2-amine (21). According to GP 2,
the title compound was prepared from 4-fluorophenylhydrazine (9)
(126 mg, 1.00 mmol), 4-bromoaniline (12) (3.44 g, 20.0 mmol), and
MnO2 (435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 21 (119 mg, 0.45 mmol, 45%): brown
amorphous solid; mp 73−74 °C; Rf = 0.5 (hexane/EtOAc = 4:1)
(UV); 1H NMR (600 MHz, CDCl3) δ 3.93 (bs, 2 H), 6.65 (d, J = 8.5
Hz, 1 H), 7.13 (t, J = 8.8 Hz, JHF = 8.8 Hz, 2 H), 7.21 (d, J = 2.3 Hz, 1
H), 7.24 (dd, J = 2.3 Hz, J = 8.5 Hz, 1 H), 7.38 (dd, JHF = 5.4 Hz, J =
8.8 Hz, 2 H); 13C NMR (91 MHz, CDCl3) δ 110.6 (Cq), 115.9 (d, JCF
= 21.4 Hz, 2 × CH), 117.4 (CH), 128.7 (Cq), 130.7 (d, JCF = 8.0 Hz, 2
4′-Chloro-5-fluorobiphenyl-2-amine (3). According to GP 2,
the title compound was prepared from 4-chlorophenylhydrazine (1)
(143 mg, 1.00 mmol), 4-fluoroaniline (2) (1.92 mL, 20.0 mmol), and
MnO2 (435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 3 as a black amorphous solid (118 mg,
0.53 mmol, 53%), mp 49−51 °C. The analytical data obtained are in
agreement with those reported in ref 11a.
3′,4′-Dichloro-5-fluorobiphenyl-2-amine (16). According to
GP 2, the title compound was prepared from 3,4-dichlorophenylhy-
drazine (5) (177 mg, 1.00 mmol), 4-fluoroaniline (2) (1.92 mL, 20.0
mmol), and MnO2 (435 mg, 5.00 mmol). Purification by column
chromatography (hexane/EtOAc = 10:1) gave 16 as a black crystalline
solid (158 mg, 0.62 mmol, 62%), mp 55−58 °C. The analytical data
obtained are in agreement with those reported in ref 11c.
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× CH), 131.2 (CH), 132.8 (CH), 133.9 (d, JCF = 3.4 Hz, Cq), 142.2
(Cq), 162.3 (d, JCF = 247.3 Hz, Cq); 19F-NMR (339 MHz, CDCl3) δ
−117.3; MS (EI) m/z 327 (10), 268 (13), 267 (81) [81Br-M+], 266
(23), 265 (91) [79Br-M+], 264 (12), 252 (43), 250 (23), 235 (27), 233
(16), 219 (16), 186 (27), 185 (100), 184 (23), 167 (19), 166 (16),
158 (11), 157 (21), 139 (11), 133 (13), 93 (22), 92 (37), 85 (19), 83
(29); HRMS (EI) calcd for C12H9BrFN [M+] 264.9902, found
264.9903.
5-Bromo-4′-chlorobiphenyl-2-amine (22). According to GP 3,
the title compound was prepared from 4-chlorophenylhydrazine
hydrochloride (1( × HCl)) (179 mg, 1.00 mmol), 4-bromoaniline
(12) (3.44 g, 20.0 mmol), NaHCO3 (420 mg, 5.00 mmol), and MnO2
(435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 22 as a black oil (152 mg, 0.54 mmol,
54%). The analytical data obtained are in agreement with those
reported in ref 11c.
5-Bromo-2′-chlorobiphenyl-2-amine (23). According to GP 2,
the title compound was prepared from 2-chlorophenylhydrazine (6)
(143 mg, 1.00 mmol), 4-bromoaniline (12) (3.44 g, 20.0 mmol) and
MnO2 (435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 23 (162 mg, 0.57 mmol, 57%): dark
brown oil; Rf = 0.4 (hexane/EtOAc = 4:1) (UV); 1H NMR (600 MHz,
CDCl3) δ 3.77 (bs, 2 H), 6.69 (d, J = 8.6 Hz, 1 H), 7.18 (d, J = 2.3 Hz,
1 H), 7.27−7.36 (m, 4 H), 7.47−7.52 (m, 1 H); 13C NMR (91 MHz,
CDCl3) δ 129.7 (Cq), 136.8 (CH), 146.8 (Cq), 146.9 (CH), 149.1
(CH), 149.5 (CH), 151.3 (CH), 151.3 (CH), 152.4 (CH), 153.3 (Cq),
156.0 (Cq), 162.0 (Cq); MS (EI) m/z (%): 285 (23), 284 (12) [37Cl-
M+], 283 (90), 282 (10) [35Cl-M+], 281 (73), 248 (73), 247 (40), 246
(69), 245 (34), 168 (37), 167 (100), 166 (71), 164 (10), 140 (28),
139 (52), 138 (10), 101 (13), 83 (40), 83 (23), 82 (20), 69 (21), 63
(11); HRMS (EI) calcd for C12H10BrClN [M+] 280.9607, found
280.9607.
4′-Chloro-5-cyanobiphenyl-2-amine (24). According to GP 3,
the title compound was prepared from 4-chlorophenylhydrazine
hydrochloride (1( × HCl)) (179 mg, 1.00 mmol), 4-amino-
benzonitrile (13) (1.18 g, 20.0 mmol), NaHCO3 (420 mg, 5.00
mmol), and MnO2 (435 mg, 5.00 mmol). Purification by column
chromatography (hexane/EtOAc = 10:1) gave 24 as reddish crystalline
solid (91.2 mg, 0.35 mmol, 35%), mp 154−157 °C. The analytical data
obtained are in agreement with those reported in ref 11c.
8.6 Hz, 2 H); 13C NMR (151 MHz, CDCl3) δ 109.9 (dd, JCF = 4.3 Hz,
JCF = 16.9 Hz, 2 × CH), 115.5 (2 × CH), 127.7 (2 × CH), 128.4 (Cq),
137.3 (dt, JCF = 4.4 Hz, JCF = 8.0 Hz, Cq), 138.4 (td, JCF = 15.5 Hz, JCF
= 250.0 Hz, Cq), 146.5 (Cq), 151.3 (ddd, JCF = 4.4 Hz, JCF = 9.9 Hz,
JCF = 248.5 Hz, 2 × Cq); 19F NMR (339 MHz, CDCl3) δ −138.0,
−167.7; MS (EI) m/z 272 (14), 270 (47), 268 (26), 235 (27), 233
(15) [M+], 224 (13), 223 (100), 219 (10), 195 (10), 85 (44), 83 (62);
HRMS (EI) calcd for C12H8F3N [M+] 223.0609, found 223.0610.
4′-Chlorobiphenyl-2-amine (27). According to GP 2, the title
compound was prepared from 4-chlorophenylhydrazine (1) (143 mg,
1.00 mmol), aniline (15) (1.82 mL, 20.0 mmol), and MnO2 (435 mg,
5.00 mmol). Purification of the regioisomers by column chromatog-
raphy (hexane/EtOAc = 10:1 → 4:1) gave 27 as a dark brown
amorphous solid (83.9 mg, 0.41 mmol, 41%)33 (mp 37−38 °C) and
4′-chlorobiphenyl-4-amine (27′) as a black oil (26.2 mg, 0.13 mmol,
13%).11c The analytical data obtained for 27 and 27′ are in agreement
with those reported in refs 11c and 33.
2′-Chlorobiphenyl-2-amine (28). According to GP 2, the title
compound was prepared from 2-chlorophenylhydrazine (6) (143 mg,
1.00 mmol), aniline (15) (1.82 mL, 20.0 mmol), and MnO2 (435 mg,
5.00 mmol). Purification of the regioisomers by column chromatog-
raphy (hexane/EtOAc = 10:1 → 4:1) gave 2′-chlorobiphenyl-4-amine
(28′) as a black oil (41.8 mg, 0.21 mmol, 21%) and 28 as a black
amorphous solid (98.7 mg, 0.49 mmol, 49%) (mp 52−53 °C). The
analytical data obtained for 28 are in agreement with those reported in
ref 31e. 2′-Chlorobiphenyl-4-amine (28′): Rf = 0.3 (hexane/EtOAc =
4:1) (UV); 1H NMR (600 MHz, CDCl3) δ 3.73 (bs, 2 H), 6.73 (d, J =
8.6 Hz, 2 H), 7.21 (ddd, J = 1.8 Hz, J = 7.3 Hz, J = 7.9 Hz, 1 H), 7.25−
7.28 (m, 3 H), 7.31 (dd, J = 1.8 Hz, J = 7.4 Hz, 1H), 7.43 (dd, J = 1.1
Hz, J = 7.9 Hz, 1H); 13C NMR (91 MHz, CDCl3) δ 114.5 (2 × CH),
126.7 (CH), 127.8 (CH), 129.6 (Cq), 129.9 (CH), 130.4 (2 × CH),
131.3 (CH), 132.5 (Cq), 140.5 (Cq), 145.9 (Cq); MS (EI) m/z 205
(32) [37Cl-M+], 204 (13), 203 (100) [35Cl-M+], 168 (11), 167 (21),
139 (8), 115 (6), 101 (6), 83 (10), 44 (25); HRMS (EI) calcd for
C12H10ClN [M+] 203.0502, found 203.0502.
2-(4-Chlorophenyl)furan (29). According to GP 3, the title
compound was prepared from 4-chlorophenylhydrazine hydrochloride
(1( × HCl)) (179 mg, 1.00 mmol), furan (2.90 mL, 40.0 mmol),
NaHCO3 (420 mg, 5.00 mmol), and MnO2 (435 mg, 5.00 mmol).
Purification by column chromatography (hexane/EtOAc = 19:1) gave
29 as an orange crystalline solid (110 mg, 0.62 mmol, 62%) (mp 80−
85 °C). The analytical data obtained are in agreement with those
reported in ref 22.
4′-Chlorobiphenyl-2-ol (30). Method a (Scheme 1): According
to GP 3, the title compounds were prepared from 4-chlorophenylhy-
drazine hydrochloride (1( × HCl)) (179 mg, 1.00 mmol), phenol
(1.88 g, 20.0 mmol), NaHCO3 (420 mg, 5.00 mmol), and MnO2 (435
mg, 5.00 mmol). Purification by column chromatography (hexane/
EtOAc = 10:1) gave 30 (60.2 mg, 0.29 mmol, 29%)34 and 30′ (19.0
mg, 0.09 mmol, 9%).35 The analytical data obtained are in agreement
with those reported in refs 34 and 35.
4′-Chloro-5-methoxybiphenyl-2-amine (25). According to GP
2, the title compound was prepared from 4-chlorophenylhydrazine (1)
(143 mg, 1.00 mmol), p-anisidine (14) (2.46 g, 20.0 mmol), and
MnO2 (435 mg, 5.00 mmol). Purification by column chromatography
(hexane/EtOAc = 10:1) gave 25 as a brown oil (91.2 mg, 0.39 mmol,
39%). The analytical data obtained are in agreement with those
reported in ref 11a.
3′,4′,5′-Trifluorobiphenyl-2-amine (26). According to GP 2, the
title compound was prepared from 3,4,5-trifluorophenylhydrazine (10)
(146 mg, 0.90 mmol), aniline (15) (1.64 mL, 18.0 mmol) and MnO2
(392 mg, 4.50 mmol). Purification of the regioisomers by column
chromatography (hexane/EtOAc = 10:1 → 4:1) gave 26 (118 mg,
0.53 mmol, 59%) and 3′,4′,5′-trifluorobiphenyl-4-amine (26′) (32.5
mg, 0.15 mmol, 16%). 3′,4′,5′-Trifluorobiphenyl-2-amine (26): brown
crystalline solid; mp 69−72 °C; Rf = 0.6 (hexane/EtOAc = 4:1) (UV);
1H NMR (360 MHz, CDCl3) δ 3.79 (bs, 2 H), 6.77 (dd, J = 0.8 Hz, J
= 8.0 Hz, 1 H), 6.83 (dt, J = 1.0 Hz, J = 7.5 Hz, 1 H), 7.06 (dd, J = 1.6
Hz, J = 7.6 Hz, 1 H), 7.07−7.13 (m, 2 H), 7.19 (ddd, J = 1.6 Hz, J =
7.4 Hz, J = 8.0 Hz, 1 H); 13C NMR (151 MHz, CDCl3) δ 113.2 (dd,
JCF = 4.5 Hz, JCF = 16.4 Hz, 2 × CH), 116.0 (CH), 118.9 (CH), 124.4
(d, JCF = 1.0 Hz, Cq), 129.4 (CH), 130.1 (CH), 135.5 (dt, JCF = 4.9
Hz, JCF = 7.9 Hz, Cq), 138.9 (td, JCF = 15.3 Hz, JCF = 251.6 Hz, Cq),
143.2 (Cq), 151.3 (ddd, JCF = 4.4 Hz, JCF = 9.9 Hz, JCF = 250.5 Hz, 2 ×
Cq); 19F-NMR (339 MHz, CDCl3) δ −137.1, −165.4; MS (EI) m/z
268 (23), 266 (13), 224 (15), 223 (100) [M+], 222 (26), 221 (12),
204 (12), 203 (18), 85 (21), 83 (30); HRMS (EI) calcd for C12H8F3N
[M+] 223.0609, found 223.0609. 3′,4′,5′-Trifluorobiphenyl-4-amine
(26′): brown crystalline solid; mp 75−80 °C; Rf = 0.2 (hexane/EtOAc
= 4:1) (UV); 1H NMR (360 MHz, CDCl3) δ 3.82 (bs, 2 H), 6.74 (d, J
= 8.7 Hz, 2 H), 7.11 (dd, J = 6.5 Hz, JHF = 9.3 Hz, 2 H), 7.31 (d, J =
Method b (Scheme 1): To a stirred suspension of phenol (1.88 g,
20.0 mmol), aqueous NaOH (8 M, 3.13 mL, 25.0 mmol), and MnO2
(435 mg, 5.00 mmol) in acetonitrile (5 mL) at rt was added 4-
chlorophenylhydrazine hydrochloride (1( × HCl)) (179 mg, 1.00
mmol) in portions over a period of 10 min. After completion of the
reaction, as monitored by TLC, the reaction mixture was filtered over
Celite. The filter cake was further washed with ethyl acetate. The
organic layer was washed with water (30 mL) and saturated aqueous
NaCl and dried over Na2SO4. The solvent was removed under reduced
pressure. The remaining substrate was removed by Kugelrohr
distillation and purification by column chromatography (hexane/
EtOAc = 10:1) gave 30 as a brown amorphous solid (81.9 mg, 0.40
mmol, 40%)34 (mp 45−47 °C) and 30′ as a brown amorphous solid
(34.9 mg, 0.17 mmol, 17%)35 (mp 130−135 °C). The analytical data
obtained are in agreement with those reported in refs 34 and 35.
4′-Chloro-2-methoxybiphenyl (31). According to GP 3, the title
compounds were prepared from 4-chlorophenylhydrazine hydro-
chloride (1( × HCl)) (179 mg, 1.00 mmol), anisole (2.18 mL, 20.0
mmol), NaHCO3 (420 mg, 5.00 mmol), and MnO2 (435 mg, 5.00
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mmol). Purification by column chromatography (100% hexane) gave
31 as a yellow amorphous solid (53.7 mg, 0.25 mmol, 25%) (mp 50−
52 °C),36 along with a mixture of 4'-chloro-3-methoxybiphenyl (8.7
mg, 0.04 mmol, 4%)37 and 4'-chloro-4-methoxybiphenyl (10.9 mg,
0.05 mmol, 5%).38 The analytical data obtained are in agreement with
those reported in refs 36−38.
AUTHOR INFORMATION
Corresponding Author
*E-mail: markus.heinrich@medchem.uni-erlangen.de.
Notes
■
The authors declare no competing financial interest.
Synthesis of 5-Fluoro-4′-methoxybiphenyl-2-amine (19)
and 2-Fluoro-4′-methoxybiphenyl-5-amine (19′) with Ammo-
nium Cerium(IV) Nitrate (Scheme 2). To a stirred solution of 4-
methoxyphenylhydrazine hydrochloride (8( × HCl)) (175 mg, 1.00
mmol) and 4-fluoroaniline (2) (555 mg, 5.00 mmol) in water (10 mL)
and HCl (10%, 2 mL) at rt was added dropwise a solution of
ammonium cerium(IV) nitrate (2.19 g, 4.00 mmol) in water (4 mL)
over a periode of 15 min. Stirring was continued for further 15 min,
the solution was diluted with water (30 mL), and Na2SO3 was used to
adjust the pH to a value of 7. The resulting mixture was extracted with
diethyl ether, and the combined organic phases were washed with
saturated aqueous NaCl and dried over Na2SO4. The solvent was
removed under reduced pressure. The remaining substrate was
removed by Kugelrohr distillation, and purification by column
chromatography (pentane/EtOAc = 3:1) gave 19 as a brown oil (39
mg, 0.18 mmol, 18%) and 19′ as a brown oil (30 mg, 0.14 mmol,
14%). 2-Fluoro-4′-methoxybiphenyl-5-amine (19′): Rf = 0.3 (pentane/
ACKNOWLEDGMENTS
■
We thank Dr. Sarah Hofling and Dr. Alexander Wetzel for
̈
preliminary experiments related to this project and Artur
Kessler for his help with GC analysis. We are grateful to Dr.
Zierke (Crop Protection, BASF SE, Ludwigshafen) for a sample
of compound 44 and interesting discussions. The financial
support of Hannelore Jasch by the Graduate School of
Molecular Science and the Deutsche Forschungsgemeinschaft
(DFG) is gratefully acknowledged.
REFERENCES
■
(1) Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339.
(2) For a review article on the Gomberg−Bachmann reaction, see:
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(a) Bolton, R.; Williams, G. H. Chem. Soc. Rev. 1986, 15, 261.
(b) Studer, A. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: New York, 2001; p 44. (c) Bowman, W. R.; Storey,
J. M. D. Chem. Soc. Rev. 2007, 36, 1803. (d) Vaillard, S. E.; Schulte, B.;
Studer, A. In Modern Arylation Methods; Ackermann, L., Ed.; Wiley-
VCH: New York, 2009; p 475.
(4) Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-
Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594.
(5) (a) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis,
2nd ed.; Wiley-VCH: New York, 2004. (b) de Meijere, A.; Diederich,
F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH:
New York, 2004. (c) Bonin, H.; Fouquet, E.; Felpin, F.-X. Adv. Synth.
Catal. 2011, 353, 3063.
(6) For recent review articles on C−H activation, see: (a) Dyker, G.
Handbook of C−H Transformations; Wiley-VCH: New York, 2005.
(b) Ackermann, L. Top. Organomet. Chem. 2008, 24, 35. (c) Li, B.-J.;
Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (d) Lersch, M.; Tilset, M.
Chem. Rev. 2005, 105, 2471.
(7) Chaturbhuj, G. U.; Akamanchi, K. G. Tetrahedron Lett. 2011, 52,
4950.
(8) For comparable radical arylations of benzene, see: (a) Curran, D.
P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706. (b) Demir, A. S.;
1
EtOAc = 3:1) (UV); H NMR (360 MHz, CDCl3) δ 3.85 (s, 3 H),
6.88 (ddd, J = 3.0 Hz, JHF = 3.8 Hz, J = 8.9 Hz, 1 H), 6.71 (dd, J = 3.0
Hz, JHF = 6.6 Hz, 1 H), 6.93 (dd, J = 8.7 Hz, JHF = 10.3 Hz, 1 H), 6.96
(d, J = 8.9 Hz, 2 H), 7.46 (dd, J = 1.6 Hz, J = 8.9 Hz, 2 H); 13C NMR
(151 MHz, CDCl3) δ 55.3 (CH3), 113.8 (2 × CH), 114.7 (d, JCF = 7.8
Hz, CH), 116.5 (d, JCF = 22.4 Hz, CH), 116.6 (d, JCF = 5.0 Hz, CH),
128.5 (d, JCF = 1.3 Hz, Cq), 129.0 (d, JCF = 14.7 Hz, Cq), 130.0 (2 ×
CH), 142.4 (d, JCF = 2.5 Hz, Cq), 153.4 (d, JCF = 237.5 Hz, Cq), 159.2
(Cq); MS (EI) m/z 217 (100) [M+], 202 (41), 175 (4), 174 (25), 146
(8), 109 (5), 93 (6), 63 (3), 44 (7).
N-(3′,4′,5′-Trifluorobiphenyl-2-yl)-3-difluoromethyl-1-meth-
yl-1H-pyrazole-4-carboxamide (45). To a stirred solution of
3′,4′,5′-trifluorobiphenyl-2-amine (26) (100 mg, 0.45 mmol) and
pyridine (65 μL, 0.81 mmol) in toluene (1 mL) at 55 °C was added
dropwise a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-
carboxylic acid chloride (44) (87.9 mg, 0.45 mmol) in toluene (300
μL) over a period of 10 min. After completion of the reaction, as
monitored by TLC, the solution was heated to 70 °C and was washed
with HCl (2 N), saturated aqueous NaHCO3, and water. After being
cooled to rt, the solution was dried over Na2SO4 and the solvent was
removed under reduced pressure. Purification by column chromatog-
raphy (hexane/EtOAc = 2:1) gave 45 (158 mg, 0.41 mmol, 92%):
white amorphous solid; mp 137−140 °C; Rf = 0.4 (hexane/EtOAc =
̈
Reis, O.; Emrullahoglu, M. J. Org. Chem. 2003, 68, 578. (c) Demir, A.
̈
̈
S.; Reis, O.; Ozgul-Karaaslan, E. J. Chem. Soc., Perkin Trans. 1 2001,
3042. (d) Jasch, H.; Hofling, S. B.; Heinrich, M. R. J. Org. Chem. 2012,
77, 1520.
̈
1:1) (UV); 1H NMR (360 MHz, CDCl3) δ 3.92 (s, 3 H), 6.65 (t, JHF
=
̈
54.2 Hz, 1 H), 6.92−7.06 (m, 2 H), 7.19−7.25 (m, 2 H), 7.38−7.47
(m, 1 H), 7.81 (bs, 1 H), 7.95 (s, 1 H), 8.19 (d, J = 8.2 Hz, 1 H); 13C
NMR (151 MHz, CDCl3) δ 39.5 (CH3), 111.6 (t, JCF = 232.9 Hz,
CH), 113.7 (dd, JCF = 4.7 Hz, JCF = 16.6 Hz, 2 × CH), 116.5 (Cq),
123.4 (CH), 125.2 (CH), 129.2 (CH), 130.0 (CH), 131.2 (Cq), 134.1
(dt, JCF = 4.9 Hz, JCF = 7.9 Hz, Cq), 134.5 (CH), 136.1 (Cq), 139.5 (td,
JCF = 15.3 Hz, JCF = 252.5 Hz, Cq), 142.3 (t, JCF = 29.3 Hz, Cq), 151.2
(ddd, JCF = 4.3 Hz, JCF = 10.0 Hz, JCF = 251.2 Hz, 2 × Cq), 159.4 (Cq);
19F NMR (339 MHz, CDCl3) δ −111.8, −136.9, −164.7; MS (EI) m/
z 382 (20), 381 (96) [M+], 222 (5), 221 (11), 160 (35), 159 (100),
139 (10), 83 (5), 44(4), 43 (14); HRMS (EI) calcd for C18H12F5N3O
[M+] 381.0901, found 381.0901.
(9) For the rate of addition of aryl radicals to benzene, see: Scaiano, J.
C.; Stewart, L. C. J. Am. Chem. Soc. 1983, 105, 3609.
(10) (a) Studer, A.; Curran, D. Angew. Chem., Int. Ed. 2011, 50, 5018
and references cited therein. (b) Yanagisawa, S.; Ueda, K.; Taniguchi,
T.; Itami, K. Org. Lett. 2008, 10, 4673.
(11) (a) Wetzel, A.; Ehrhardt, V.; Heinrich, M. R. Angew. Chem., Int.
Ed. 2008, 47, 9130. (b) Hofling, S. B.; Bartuschat, A. L.; Heinrich, M.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for new compounds 17−19, 21, 23,
26, 28, and 45 and 1H NMR spectra for known compounds 3,
16, 20, 22, 24, 25, 27, and 29−31. This material is available free
of charge via the Internet at http://pubs.acs.org/.
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