Oxidative radical arylation of anilines with arylhydrazines and dioxygen from air

Article abstract of DOI:10.1021/jo500063r

Substituted 2-aminobiphenyls have been prepared from arylhydrazine hydrochlorides and anilines in biphasic radical arylation reactions with dioxygen from air as a most simple and readily available oxidant. Under optimized conditions, the free amino functionality of the aniline leads to high ortho:meta regioselectivities, now even for anilines bearing a donor substituent in the para position. Finally, the mild and metal-free new access to aminobiphenyls was shown to be applicable on a gram scale.

Full text of DOI:10.1021/jo500063r

Note
pubs.acs.org/joc
Oxidative Radical Arylation of Anilines with Arylhydrazines and
Dioxygen from Air
Josefa Hofmann, Hannelore Jasch, 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 arylhydrazine hydrochlorides and anilines in biphasic radical
arylation reactions with dioxygen from air as a most simple and
readily available oxidant. Under optimized conditions, the free
amino functionality of the aniline leads to high ortho:meta
regioselectivities, now even for anilines bearing a donor substituent
in the para position. Finally, the mild and metal-free new access to
aminobiphenyls was shown to be applicable on a gram scale.
ubstituted biphenyls are valuable building blocks in many
reactions, which are aryl diazonium salts,15 remarkable advances
Sfields of application. One particularly important subgroup have recently been achieved by employing photocatalysts16 and
1
optimized Gomberg−Bachmann conditions.17 In addition,
bromo- and iodobenzenes, which had for decades been mainly
applied in combination with organostannanes,18 have now been
shown to be valuable aryl radical sources for the preparation of
biphenyls under metal-free conditions.19,20 Regarding aryl
radical acceptors, unsubstituted benzene is still the most widely
used compound due to the negligibility of regioselectivity
issues.21 In this context, we have recently discovered that
anilines are not only highly reactive scavengers for aryl radicals,
thereby exceeding the capabilities of phenols, phenyl ethers,
and nitrobenzenes,22 but they do allow arylations to proceed
with unprecedented regioselectivities.17,23 Based the advantages
of such substrates, we now report the metal-free arylation of
anilines using arylhydrazines as radical sources and dioxygen
from air as simple oxidant under mild conditions. In general,
radical arylations with arylhydrazines have so far required either
pure oxygen atmosphere and catalysts,24 an excess of an
oxidizing agent,23,25 or harsh conditions.26 Another aspect that
will facilitate future applications is that arylhydrazines are
readily available from aryldiazonium salts by reduction with
such simple reagents as sodium sulfite.27
The oxidation of arylhydrazines that leads to aryl radicals via
the intermediate formation of instable diazenes has been known
for a long time and studied intensively.28 Beneficially, such
oxidations of arylhydrazines can be carried out under mild
conditions and also at low temperatures.29 Our first experi-
ments under air atmosphere (Table 1, entries 1 and 2) revealed
that relatively long reaction times of 60 h are required at room
temperature and that chlorobenzene (4), arising from hydrogen
abstraction by the aryl radical, is formed as major byproduct.15
of compounds are 2-aminobiphenyls,2 which for example, occur
as core structures of the three industrially produced fungizides
boscalid, bixafen, and Xemium (Figure 1).3−5 Not surprisingly,
the large-scale syntheses of these compounds rely on
organometallic cross-coupling reactions as key steps.6−8
Figure 1. Boscalid, bixafen, and Xemium.
Since radical arylation reactions9 can basically offer a much
more straightforward access to substituted biphenyls, mainly
due to the fact that such arylations are comparable to C−H
activation reactions10,11 and less functionalized starting
materials are therefore required, there has recently been
increasing interest in improving the reaction type that was
first reported by Gomberg and Bachmann about 90 years ago.12
Important challenges are, in particular, to conduct radical
arylations with high regioselectivity13 and to lower the excess of
the arene acting as aryl radical acceptor. Large amounts of aryl
radical acceptor are commonly required to counterbalance the
relatively slow addition of aryl radicals to most functionalized
benzene derivatives.14 Moreover, new reactions should be
sustainable and ideally be feasible under metal-free conditions.
Based on the traditional aryl radical sources for arylation
Received: January 10, 2014
Published: February 13, 2014
© 2014 American Chemical Society
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Note
Table 1. Optimization of Reaction Conditions for Neat
Reactions in Aniline
Table 2. Optimization of Reaction Conditions for Biphasic
Reactions
b
aminobiphenyl 3
chlorobenzene 4
(%)
aminobiphenyl chlorobenzene
a
a
b
entry
conditions
(%)
entry
conditions
3
(%)
4 (%)
c
c
1
2
3
4
5
6
7
rt, 18 h
rt, 60 h
20
25
1
2
3
4
5
rt, 60 h, NaOH (1 M)
rt, 60 h, NH3 (1 M)
54
27
25
30
25
c
c
53
38
46
50
55
68
d
e
rt, 60 h, stream of air
60 °C, 24 h
60 °C, 24 h, 5 equiv of H2O
60 °C, 24 h, 20 equiv of H2O
39
nd
rt, 60 h, Na2CO3 (0.5 M)
60 °C, 24 h, NaOH (1 M)
60 °C, 24 h, NaOH (1 M), slow
addition of 1 over 9 h
46
49
49
61
46
50
40
37
c
c
15
a
60 °C, 24 h, addition of 1
Standard conditions: 4-chlorophenylhydrazine hydrochloride (1 ×
HCl) (1 mmol), 4-fluoroaniline (2) (20 mmol), H2O (1 mL) under
over 4 h
b
air. Yield determined by 1H NMR referenced to 4-fluoroaniline.
8
9
60 °C, 24 h, addition of 1
55
35
over 9 h
c
Yield determined by 1H NMR using dimethyl terephthalate as
c
c
12 min, air, micromixer
0
0
internal standard.
a
Standard conditions: 4-chlorophenylhydrazine (1) (1 mmol), 4-
b
fluoroaniline (2) (20 mmol) under air. Yields determined by 1H
synthetic access to biphenyls. In a first row of experiments a
variety of substituted arylhydrazine hydrochlorides (1, 5−10)
was reacted with 4-fluoroaniline (2) (Table 3, entries 1−7).
c
NMR using dimethyl terephthalate as internal standard. Yield
d
determined by 1H NMR referenced to 4-fluoroaniline. Yield
e
determined after purification by column chromatography. Not
detected due to volatility of 4 in the stream of air.
Table 3. Oxidative Arylation: Scope and Limitations
While passing a stream of air through the reaction mixture did
not significantly reduce the reaction time (entry 3), this was
achieved by raising the temperature to 60 °C (entry 4).
Attempts to decrease the amount of undesired chlorobenzene
(4) through the addition of water, which can potentially
stabilize the N−H bonds in the aniline and hydrazine by
hydrogen bonding,30 did not lead to improved product ratios of
3:4 (entries 5 and 6). Since previous studies had given a hint
that arylhydrazines are far more susceptible to hydrogen atom
abstraction than anilines,23,31 hydrazine 1 was then added to the
reaction mixture in five batches over 4 h. Based on the now
improved ratio of 61:37 for 3:4 (entry 7), we tried to further
exploit this effect by adding 1 even more slowly in 10 batches
over 9 h (entry 8). The observation that the yield of 3 could
not be further increased appeared to be due to a partial
decomposition of the phenylhydrazine 1 under air, prior to the
addition to the reaction mixture. An exemplary attempt to run
the reaction in a microreactor failed completely (entry 9).
Having observed a remarkable instability of the arylhydra-
zines under air, which is crucial in the reaction mixture but an
undesired property before addition, we turned to explore the
use of the corresponding air-stable hydrazine hydrochloride 1
(×HCl). Upon addition of the hydrochloride 1 to biphasic
mixtures of the aniline 2 and different inorganic bases in water
(Table 2, entries 1−3), the best results were obtained for
sodium hydroxide. Raising the reaction temperature to 60 °C
again shortened the reaction time (entry 4), and the slow
addition of 1 had the beneficial effect of further lowering the
amount of undesired chlorobenzene (4). When the ratios of 3:4
in all biphasic attempts (Table 2) are compared with those
observed in the homogeneous reactions (Table 1), hydrogen
abstraction by the aryl radical appears to be less pronounced in
aqueous biphasic systems.
a,b
entry
hydrazine: R1 =
aniline: R2 =
aminobiphenyl (%)
1
1: 4-Cl
5: H
2: F
3 (55)
2
2: F
17 (48)
3
6: 4-F
2: F
18 (53)
4
7: 3,4,5-F3
8: 3,4-Cl2
9: 4-CN
10: 4-OMe
1: 4-Cl
1: 4-Cl
1: 4-Cl
1: 4-Cl
1: 4-Cl
1: 4-Cl
2: F
19 (24)
5
2: F
20 (44)
6
2: F
21 (49)
7
2: F
22 (35)
8
11: H
12: Cl
13: Br
14: CN
15: OMe
16: OEt
23 (60, o:p = 51:9)
24 (47)
9
10
11
12
13
25 (57)
26 (27)
27 (42)
28 (30)
a
Standard conditions: hydrazine hydrochloride 1, 5−10 (1 mmol,
slowly added to the reaction mixture in 10 batches over 9 h), aniline 2,
11−16 (20 mmol), NaOH (1M, 1 mL). Isolated yields after
b
purification by column chromatography.
Moderate to good yields were obtained for most substitution
patterns on the arylhydrazine with two exceptions. The
aromatic core of 3,4,5-trifluorophenylhydrazine (7) is probably
too strongly activated toward nucleophilic substitution so that
homocoupling of 7 (e.g., via the hydrazine unit acting as
nucleophile) competes with the desired, but not too rapid,
oxidation of the hydrazine. The fact that anisole was observed
as the major product (60% yield) in the reaction of the
electron-rich 4-methoxyphenylhydrazine (10) points to the
With optimized conditions available, we then turned to
investigate the scope and the limitations of this metal-free
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Note
increased tendency of para-donor-substituted aryl radicals to
stabilize themselves via hydrogen abstraction (entry 7). This
effect was somehow unexpected since only methoxy groups in
the ortho position were so far known to modify the reactivity of
an aryl radical through their negative inductive effect on the
carbon sceleton.32 Substituents in the para-position, even with
strong mesomeric effects, usually do not significantly change
the reactivity of the aryl radical since it is located in an sp2
orbital which shows no major overlap with the conjugated π
system.
1). Aminobiphenyl 23 represents a key buildling block for the
fungicide boscalid and is currently produced through
Scheme 1. Synthesis of 2-Aminobiphenyl 23 on a Larger
Scale
In a second row of experiments, 4-chlorophenylhydrazine
(1) was reacted with six different anilines (Table 3, entries 8−
13). The results clearly indicate that halogen-substituted
unpolar anilines, including nonfunctionalized aniline (11), are
the preferred substrates for the oxidative arylation reaction
(entries 8−10). Two repetitions of the experiment leading to
aminobiphenyl 23 (entry 8) gave yields of 57% (o:p = 44:13)
and 68% (o:p = 55:13), thus demonstrating a reasonable
reproducibility. Lower yields were obtained with the 4-cyano, 4-
methoxy, and 4-ethoxy derivatives 14−16 (entries 11−13).
Since no major products other than the desired 2-amino-
biphenyls 26−28 could be detected after recovery of the excess
of aniline by Kugelrohr distillation and only volatile side
products had thus been formed, the nitrile or alkoxy groups
apparently led to increased hydrogen abstraction by the aryl
radical. This could to a certain degree be due to a simple
polarity effect in the sense that there is a less distinct phase
separation which in turn makes the reaction conditions more
comparable to the homogeneous variant (Table 1). These
conditions had previously led to increased hydrogen
abstraction. The explanation that a radical-stabilizing sub-
stituent in the para-position of the aniline, such as alkoxy or
cyano, could increase the hydrogen atom donor capabilities of
the amino group due to the formation of a related nitrogen-
centered “benzylic” radical33 appears less probable since
nonvolatile products should arise from that side reaction.
Remarkably, no regioisomers resulting from an attack of the
aryl radical in 3-position of aniline could be detected in the
palladium-catalyzed cross-coupling of 2-chloronitrobenzene
and 4-chlorophenylboronic acid.7
A plausible reaction mechanism for all arylations described
above is depicted in Scheme 2. After a rapid formation of the
Scheme 2. Plausible Reaction Mechanism for the Formation
of 2-Aminobiphenyls
free phenylhydrazine 34 from its hydrochloride salt 31 a slow
oxidation to a phenyldiazene 35 occurs. The diazene 35 is then
rapidly converted to an aryl radical 36 in the presence of
oxygen,28 and its addition to an aniline 32 provides the
cyclohexadienyl intermediate 37. Final oxidation of 37, which is
again known to be fast in presence of oxygen,34 leads to 2-
aminobiphenyls 33. Representing a key element of the process,
the only slow step from hydrazine 34 to diazene 35 requires a
slow addition of the hydrochloride 31 to the reaction mixture
to minimize hydrogen abstraction from 34 by the aryl radical
36.
1
reaction mixtures by H NMR analysis. We therefore estimate
the ortho:meta regioselectivity of the aniline arylation to be at
least 20:1. Such high regioselectivities were especially surprising
for 4-anisidine (15) and 4-phenetidine (16), since previous
studies with these substrates had shown that an additional
donor substitutent on the aniline can significantly decrease the
ortho:meta regioselectivity to ratios of only 3.5:1.17
In summary, we have described an improved, now metal-free
access to 2-aminobiphenyls using anilines, arylhydrazines, and
air as oxidant. The directing effect of the unprotonated amino
functionality leads to product formation with high regiose-
lectivity. From a synthetic standpoint, advantages of the new
methodology result from the use of cheap and readily available
starting materials as well as sustainable and mild conditions.
Since the arylation reactions are particularly well suited for
arylhydrazines and anilines bearing halogen atoms, they are
moreover a valuable extension to known palladium-catalyzed
cross-coupling reactions.
The strong directing effect of the amino group in anilines,
which is probably further supported by a stabilizing effect of the
amino group on the intermediate cyclohexadienyl radical (cf.
37, Scheme 2), is currently our only explanation for the high
regioselectivity. The magnitude of these effects also became
apparent in a comparative experiment with 4-fluoroanisole
(29). Under otherwise identical conditions, and with 4-
chlorophenylhydrazine (1) as aryl radical source, the ortho
and meta arylation products 30 and 30′ were formed in yields
of 36% and 9%, respectively, and thus with much less
regioselectivity.
We further investigated the feasibility of the metal-free
radical arylation on a larger, 20-fold scale. Starting from 4-
chlorophenylhydrazine hydrochloride 1 (×HCl) and aniline
(11), the desired 4′-chlorobiphenyl-2-amine (23) was obtained
in a yield of 43% (cf. 51% in Table 3, entry 8) along with 9% of
its regioisomer 4′-chlorobiphenyl-4-amine after distillative
recovery of aniline (11) and column chromatography (Scheme
EXPERIMENTAL SECTION
Solvents and reagents were 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. Chemical shifts are given in parts per million
(ppm). 19F NMR spectra were recorded at 338.8 MHz using CFCl3 (0
■
1
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The Journal of Organic Chemistry
Note
ppm) or C6F6 (−164.9 ppm) as standard. Chemical shifts are reported
in parts per million (ppm). Coupling constants are in reported 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 electron impact (EI). A sector field mass analyzer was
used for HRMS measurements. Analytical TLC was carried out on
Merck silica gel plates using short wave (254 nm) UV light and
KMnO4 to visualize components. Silica gel (Kieselgel 60, 40−63 μm,
Merck) was used for flash column chromatography.
(600 MHz, CDCl3) δ 6.69 (dd, JHF = 4.8 Hz, J = 8.7 Hz, 1 H), 6.83
(dd, J = 3.0 Hz, JHF = 9.2 Hz, 1 H), 6.84−6.89 (m, 1 H), 7.13 (t, J =
8.7 Hz, JHF = 8.7 Hz, 2 H), 7.40 (dd, JHF = 5.4 Hz, J = 8.8 Hz, 2 H);
13C NMR (91 MHz, CDCl3) δ 115.0 (d, JCF = 22.3 Hz, CH), 115.8 (d,
J
CF = 21.4 Hz, 2 × CH), 116.6 (d, JCF = 7.7 Hz, CH), 116.7 (d, JCF =
22.5 Hz, CH), 127.7 (d, JCF = 7.2 Hz, Cq), 130.6 (d, JCF = 8.0 Hz, 2 ×
CH), 134.4 (dd, JCF = 1.6 Hz, JCF = 3.3 Hz, Cq), 139.4 (d, JCF = 2.3
Hz, Cq), 156.3 (d, JCF = 237.5 Hz, Cq), 162.3 (d, JCF = 247.2 Hz, Cq).
The analytical data obtained are in agreement with those reported in
ref 17.
Starting materials: hydrazine hydrochlorides 1, 5, 9, and 10 and all
anilines 2 and 11−16 were commercially available.
3′,4′,5′,5-Tetrafluorobiphenyl-2-amine (19). Compound 19 was
prepared from 4-fluoroaniline (1.92 mL, 20.0 mmol) and 3,4,5-
trifluorophenylhydrazine hydrochloride (199 mg, 1.00 mmol)
according to the general procedure at 60 °C. The excess of 4-
fluoroaniline was removed by Kugelrohr distillation in vacuo at 80 °C.
Purification by column chromatography gave 19 (57.0 mg, 0.24 mmol,
General Procedure for the Synthesis of Arylhydrazine
Hydrochlorides.23 To a solution of the aniline (10.0 mmol) in
acetic acid (5.0 mL) was added concentrated hydrochloric acid (10
mL) at room temperature. After cooling to 0 °C, a solution of NaNO2
(830 mg, 12.0 mmol) in water (3.0 mL) was added dropwise over a
period of 20 min, and stirring at 0 °C was continued for further 30
min. A precooled solution of tin(II) chloride dihydrate (5.00 g, 22.0
mmol) in concentrated hydrochloric acid (10 mL) was added
dropwise over a period of 10 min. After 1 h of stirring at 0 °C, the
formed precipitate was collected by filtration, washed with water, and
dried in vacuo. The hydrazine hydrochloride was used without further
purification.
1
24%): dark red oil; Rf = 0.6 (hexane/EtOAc = 4:1) (UV); H NMR
(600 MHz, CDCl3) δ 6.71 (dd, JHF = 4.8 Hz, J = 8.8 Hz, 1 H), 6.80
(dd, J = 3.0 Hz, JHF = 9.0 Hz, 1 H), 6.90 (ddd, J = 3.0 Hz, JHF = 8.1 Hz,
J = 8.8 Hz, 1 H), 7.06−7.13 (m, 2 H); 13C NMR (91 MHz, CDCl3) δ
113.1 (dd, JCF = 8.9 Hz, JCF = 22.0 Hz, 2 × CH), 116.0 (d, JCF = 22.2
Hz, CH), 118.9 (d, JCF = 23.9 Hz, CH), 124.4 (d, JCF = 8.9 Hz, Cq),
129.9 (d, JCF = 7.7 Hz, CH), 130.1 (d, JCF = 1.9 Hz, Cq), 135.4 (dt, JCF
= 4.9 Hz, JCF = 7.9 Hz, Cq), 138.9 (dt, JCF = 15.2 Hz, JCF = 251.9 Hz,
Cq), 143.1 (d, JCF = 252.0 Hz, Cq), 151.6 (ddd, JCF = 4.4 Hz, JCF = 9.7
Hz, JCF = 256.1 Hz, 2 × Cq); MS (EI) m/z 241 [M+] (100), 242 (36),
240 (46), 239 (29), 222 (26), 221 (46), 220 (31), 193 (13), 120 (11),
110 (11), 18 (30); HRMS (EI) calcd for C12H7F4N [M+] 241.0515,
found 241.0515.
General Procedure for the Synthesis of 2-Aminobiphenyls
from Arylhydrazine Hydrochlorides. A mixture of the aniline
(20.0 mmol) and aqueous sodium hydroxide (1 M, 1.0 mL) was
heated to 60−90 °C, and the arylhydrazine hydrochloride was added
portionwise in 10 batches over a period of 9 h. The reactions were
completed after 24 h at the given temperature, as monitored by TLC.
After removal of water under reduced pressure, the remaining aniline
was recovered by Kugelrohr distillation, and the crude 2-amino-
biphenyls were purified by column chromatography on silica gel
(hexane/EtOAc = 8:1) unless otherwise noted.
3′,4′-Dichloro-5-fluorobiphenyl-2-amine (20). Compound 20 was
prepared from 4-fluoroaniline (1.92 mL, 20.0 mmol) and 3′,4′-
dichlorophenylhydrazine hydrochloride (214 mg, 1.00 mmol)
according to the general procedure at 60 °C. The excess of 4-
fluoroaniline was removed by Kugelrohr distillation in vacuo at 80 °C.
Purification by column chromatography gave 20 (100 mg, 0.39 mmol,
4′-Chloro-5-fluorobiphenyl-2-amine (3). Compound 3 was pre-
pared from 4-fluoroaniline (1.92 mL, 20.0 mmol) and 4-
chlorophenylhydrazine hydrochloride (179 mg, 1.00 mmol) according
to the general procedure at 60 °C. The excess of 4-fluoroaniline was
removed by Kugelrohr distillation in vacuo at 80 °C. Purification by
column chromatography gave 3 (121 mg, 0.55 mmol, 55%): dark
brown oil; Rf = 0.4 (hexane/EtOAc = 4:1) (UV); 1H NMR (360 MHz,
CDCl3) δ 6.70 (dd, JHF = 4.8 Hz, J = 8.7 Hz, 1 H), 6.83 (dd, J = 3.0
Hz, JHF = 9.2 Hz, 1 H), 6.85 (ddd, J = 3.0 Hz, JHF = 8.2 Hz, J = 8.3 Hz,
1 H), 7.38 (d, J = 8.8 Hz, 2 H), 7.43 (d, J = 8.8 Hz, 2 H); 13C NMR
(91 MHz, CDCl3) δ 115.2 (d, JCF = 22.2 Hz, CH), 116.5 (d, JCF = 22.6
Hz, CH), 116.8 (d, JCF = 7.8 Hz, CH), 127.5 (d, JCF = 7.3 Hz, Cq),
129.1 (2 × CH), 130.3 (2 × CH), 133.6 (Cq) 136.9 (d, JCF = 1.7 Hz,
Cq), 139.2 (d, JCF = 2.2 Hz, Cq), 155.1 (d, JCF = 243.9 Hz, Cq). The
analytical data obtained are in agreement with those reported in ref 17.
5-Fluorobiphenyl-2-amine (17). Compound 17 was prepared from
4-fluoroaniline (1.92 mL, 20.0 mmol) and phenylhydrazine hydro-
chloride (99.0 μL, 1.00 mmol) according to the general procedure at
60 °C. The excess of 4-fluoroaniline was removed by Kugelrohr
distillation in vacuo at 80 °C. Purification by column chromatography
1
39%): brown oil; Rf = 0.3 (hexane/EtOAc = 4:1) (UV); H NMR
(600 MHz, CDCl3) δ 6.69 (dd, JHF = 4.8 Hz, J = 8.8 Hz, 1 H), 6.81
(dd, J = 3.0 Hz, JHF = 9.0 Hz, 1 H), 6.89 (ddd, J = 3.0 Hz, JHF = 8.1 Hz,
J = 8.8 Hz, 1 H), 7.29 (dd, J = 2.0 Hz J = 8.3 Hz, 1 H), 7.52 (d, J = 8.2
Hz, 1 H), 7.55 (d, J = 2.1 Hz, 1 H); 13C NMR (91 MHz, CDCl3): δ
115.8 (d, JCF = 22.3 Hz, CH), 116.4 (d, JCF = 22.8 Hz, CH), 116.9 (d,
JCF = 7.7 Hz, CH), 125.7 (d, JCF = 7.3 Hz, Cq), 128.9 (CH), 130.8 (2
× CH), 132.1 (Cq), 133.2 (Cq), 138.4 (d, JCF = 2.5 Hz, Cq), 139.4 (d,
JCF = 2.1 Hz, Cq), 156.3 (d, JCF = 237.2 Hz, Cq). The analytical data
obtained are in agreement with those reported in ref 17.
4′-Cyano-5-fluorobiphenyl-2-amine (21). Compound 21 was
prepared from 4-fluoroaniline (1.92 mL, 20.0 mmol) and 4-
cyanophenylhydrazine hydrochloride (169 mg, 1.00 mmol) according
to the general procedure at 60 °C. The excess of 4-fluoroaniline was
removed by Kugelrohr distillation in vacuo at 80 °C. Purification by
column chromatography gave 21 (103 mg, 0.49 mmol, 49%): brown
1
crystals; mp 163−165 °C; Rf = 0.2 (hexane/EtOAc = 4:1) (UV); H
NMR (600 MHz, CDCl3) δ 6.73 (dd, JHF = 4.7 Hz, J = 8.7 Hz, 1 H),
6.83 (dd, J = 3.0 Hz, JHF = 9.1 Hz, 1 H), 6.95 (dt, J = 3.0 Hz, JHF = 8.1
Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2 H), 7.75 (d, J = 8.3 Hz, 2 H); 13C
NMR (151 MHz, CDCl3) δ 111.4 (Cq), 116.3 (d, JCF = 18.3 Hz, CH),
116.6 (d, JCF = 18.9 Hz, CH), 117.2 (d, JCF = 7.5 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), 143.1 (d, JCF = 2.0 Hz, Cq), 156.4 (d, JCF = 237.4
Hz, Cq). The analytical data obtained are in agreement with those
reported in ref 23.
gave 17 (99.0 mg, 0.48 mmol, 48%): brown oil; Rf = 0.3 (hexane/
1
EtOAc = 4:1) (UV); H NMR (600 MHz, CDCl3) δ 6.72 (dd, JHF
=
4.9 Hz, J = 9.6 Hz, 1 H), 6.85 - 6.90 (m, 2 H), 7.34−7.38 (m, 1 H),
7.42−7.47 (m, 4 H); 13C NMR (91 MHz, CDCl3) δ 114.8 (d, JCF
=
22.3 Hz, CH), 116.5 (d, JCF = 22.4 Hz, CH), 116.7 (d, JCF = 7.9 Hz,
CH), 127.6 (CH), 128.7 (d, JCF = 7.2 Hz, Cq), 128.9 (4 × CH), 138.5
(d, JCF = 1.3 Hz, Cq), 139.1 (d, JCF = 2.3 Hz, Cq), 156.4 (d, JCF = 235.4
Hz, Cq). The analytical data obtained are in agreement with those
reported in ref 17.
5-Fluoro-4′-methoxybiphenyl-2-amine (22). Compound 22 was
prepared from 4-fluoroaniline (1.92 mL, 20.0 mmol) and 4-
methoxyphenylhydrazine hydrochloride (175 mg, 1.00 mmol)
according to the general procedure at 60 °C. The excess of 4-
fluoroaniline was removed by Kugelrohr distillation in vacuo at 80 °C.
Purification by column chromatography gave 22 (76.0 mg, 0.35 mmol,
35%): dark brown oil; Rf = 0.3 (hexane/EtOAc = 4:1) (UV); 1H NMR
(600 MHz, CDCl3) δ 3.85 (s, 3 H), 6.68 (dd, JHF = 4.9 Hz, J = 9.2 Hz,
1 H), 6.80−6.70 (m, 2 H), 6.99 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 8.9
4′,5-Difluorobiphenyl-2-amine (18). Compound 18 was prepared
from 4-fluoroaniline (1.92 mL, 20.0 mmol) and 4-fluorophenylhy-
drazine hydrochloride (163 mg, 1.00 mmol) according to the general
procedure at 60 °C. The excess of 4-fluoroaniline was removed by
Kugelrohr distillation in vacuo at 80 °C. Purification by column
chromatography gave 18 (108 mg, 0.53 mmol, 53%): black crystalline
solid; mp 88−94 °C; Rf = 0.4 (hexane/EtOAc = 4:1) (UV); 1H NMR
2317
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The Journal of Organic Chemistry
Note
Hz, 2 H); 13C NMR (151 MHz, CDCl3) δ 55.3 (CH3), 114.4 (2 ×
CH), 114.6 (d, JCF = 22.3 Hz, CH), 116.2 (d, JCF = 22.3 Hz, CH),
116.6 (d, JCF = 7.8 Hz, CH), 128.2 (d, JCF = 7.5 Hz, Cq), 130.0 (2 ×
CH), 130.3 (Cq), 139.7 (d, JCF = 2.0 Hz, Cq), 156.7 (d, JCF = 236.0 Hz,
Cq), 159.4 (Cq). The analytical data obtained are in agreement with
those reported in ref 23.
removed by Kugelrohr distillation in vacuo at 120 °C. The crude
product was purified by column chromatography (hexane/EtOAc =
6:1) to give 27 (99.0 mg, 0.42 mmol, 42%): black crystalline solid; mp
1
88−92 °C; Rf = 0.6 (CH2Cl2/EtOAc = 50:1) (UV); H NMR (600
MHz, CDCl3) δ 3.77 (s, 3 H), 6.70 (d, J = 2.8 Hz, 1 H), 6.76 (d, J =
8.6 Hz, 1 H), 6.80 (dd, J = 2.8 Hz, J = 8.1 Hz, 1 H), 7.39−7.44 (m, 4
H); 13C NMR (91 MHz, CDCl3) δ 55.8 (CH3), 114.7 (Cq), 115.7
(CH), 117.1 (CH), 127.5 (CH), 129.0 (2 × CH), 130.4 (2 × CH),
133.2 (Cq), 136.9 (Cq), 137.9 (Cq), 152.9 (Cq). The analytical data
obtained are in agreement with those reported in ref 17.
4′-Chlorobiphenyl-2-amine (23) and 4′-Chlorobiphenyl-4-amine
(23′). Compounds 23 and 23′ were prepared from aniline (1.82 mL,
20.0 mmol) and 4-chlorophenylhydrazine hydrochloride (179 mg,
1.00 mmol) according to the general procedure at 60 °C. The excess
of aniline was removed by Kugelrohr distillation in vacuo at 75 °C.
Purification by column chromatography gave 23 (104 mg, 0.51 mmol,
51%) as a black solid, mp 65−67 °C, and 23′ (18.0 mg, 0.09 mmol,
9%) as a brown solid, mp 118 °C−120 °C. 4′-Chlorobiphenyl-2-amine
4′-Chloro-5-ethoxybiphenyl-2-amine (28). Compound 28 was
prepared from 4-ethoxyaniline (2.59 g, 20.0 mmol) and 4-
chlorophenylhydrazine hydrochloride (179 mg, 1.00 mmol) according
to the general procedure at 60 °C. The excess of 4-ethoxyaniline was
removed by Kugelrohr distillation in vacuo at 130 °C. The crude
product was purified by column chromatography (hexane/EtOAc =
6:1) to give 28 (80.0 mg, 0.30 mmol, 30%): black oil; Rf = 0.4
(hexane/EtOAc = 4:1) (UV); 1H NMR (600 MHz, CDCl3) δ 1.38 (t,
J = 7.0 Hz, 3 H), 3.98 (q, J = 7.0 Hz, 2 H), 6.70 (d, J = 2.8 Hz, 1 H),
6.74 (d, J = 8.6 Hz, 1 H), 6.80 (dd, J = 2.8 Hz, J = 8.1 Hz, 1 H), 7.40
(s, 4 H); 13C NMR (151 MHz, CDCl3) δ 15.0 (CH3), 64.8 (CH2),
115.7 (CH), 116.7 (CH), 117.5 (CH), 127.9 (Cq), 129.0 (2 × CH),
130.4 (2 × CH), 133.2 (Cq), 136.9 (Cq), 137.9 (Cq), 152.9 (Cq). The
analytical data obtained are in agreement with those reported in ref 17.
4′-Chloro-5-fluoro-2-methoxybiphenyl (30) and 4′-chloro-6-
fluoro-3-methoxybiphenyl (30′). Compounds 30 and 30′ were
prepared from 4-fluoroanisole (2.26 mL, 2.59 g, 20.0 mmol) and 4-
chlorophenylhydrazine hydrochloride (179 mg, 1.00 mmol) according
to the general procedure at 60 °C. The excess of 4-fluoroanisole was
removed by Kugelrohr distillation in vacuo at 110 °C. The crude
products were purified by column chromatography (silica gel, hexane/
EtOAc = 8:1) to give the regioisomers 4′-chloro-5-fluoro-2-
methoxybiphenyl (30) (86.0 mg, 0.36 mmol, 36%) as a brown oil
and 4′-chloro-6-fluoro-3-methoxybiphenyl (30′) as a brown oil (22.0
mg, 0.09 mmol, 9%). 4′-Chloro-5-fluoro-2-methoxybiphenyl (30): Rf
1
(23): Rf = 0.6 (hexane/EtOAc = 4:1) (UV); H NMR (600 MHz,
CDCl3) δ 6.76 (dd, J = 1.2 Hz, J = 8.6 Hz, 1 H), 6.86 (dt, J = 1.2 Hz, J
= 7.5 Hz, 1 H), 7.08 (dd, J = 1.6 Hz, J = 7.6 Hz, 1 H), 7.16 (ddd, J =
1.6 Hz, J = 7.4 Hz, J = 8.0 Hz, 1 H), 7.38−7.42 (m, 4 H); 13C NMR
(91 MHz, CDCl3) δ 115.6 (CH), 118.4 (CH), 126.3 (Cq), 128.7
(CH), 129.1 (2 × CH), 130.3 (CH), 130.5 (2 × CH), 133.6 (Cq),
136.9 (Cq), 143.2 (Cq). 4′-Chlorobiphenyl-4-amine (23′): Rf = 0.3
(hexane/EtOAc = 4:1) (UV); 1H NMR (600 MHz, CDCl3) δ 6.76 (d,
J = 8.6 Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H),
7.46 (d, J = 8.5 Hz, 2 H); 13C NMR (151 MHz, CDCl3) δ 115.4 (2 ×
CH), 127.4 (2 × CH), 127.9 (2 × CH), 128.7 (2 × CH), 130.2 (Cq),
132.5 (Cq), 139.8 (Cq), 146.7 (Cq). The analytical data obtained are in
agreement with those reported in ref 17.
4′,5-Dichlorobiphenyl-2-amine (24). Compound 24 was prepared
from 4-chloroaniline (2.55 g, 20.0 mmol) and 4-chlorophenylhy-
drazine hydrochloride (179 mg, 1.00 mmol) according to the general
procedure at 80 °C. The excess of 4-chloroaniline was removed by
Kugelrohr distillation in vacuo at 120 °C. Purification by column
chromatography gave 24 (140 mg, 0.47 mmol, 47%): dark brown oil;
Rf = 0.5 (hexane/EtOAc = 4:1) (UV); 1H NMR (600 MHz, CDCl3) δ
6.69 (d, J = 8.2 Hz, 1 H), 7.07 (d, J = 2.5 Hz, 1 H), 7.11 (dd, J = 2.5
Hz, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.7 Hz, 2 H), 7.41 (d, J = 8.6 Hz, 2
H); 13C NMR (91 MHz, CDCl3) δ 116.9 (CH), 124.0 (Cq), 128.3
(CH), 129.1 (2 × CH), 130.0 (2 × CH), 130.6 (CH), 131.6 (Cq),
133.5 (Cq), 136.1 (Cq), 141.8 (Cq). The analytical data obtained are in
agreement with those reported in ref 17.
5-Bromo-4′-chlorobiphenyl-2-amine (25). Compound 25 was
prepared from 4-bromoaniline (3.44 g, 20.0 mmol) and 4-
chlorophenylhydrazine hydrochloride (179 mg, 1.00 mmol) according
to the general procedure at 70 °C. The excess of 4-bromoaniline was
removed by Kugelrohr distillation in vacuo at 105 °C. Purification by
column chromatography gave 25 (160 mg, 0.57 mmol, 57%): dark
brown oil; Rf = 0.6 (hexane/EtOAc = 4:1) (UV); 1H NMR (600 MHz,
CDCl3) δ 6.76 (d, J = 8.5 Hz, 1 H), 7.25 (d, J = 2.3 Hz, 1 H), 7.30 (dd,
J = 2.3 Hz, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.7
Hz, 2 H); 13C NMR (91 MHz, CDCl3) δ 110.6 (Cq), 118.4 (CH),
129.1 (2 × CH), 130.3 (2 × CH), 130.6 (Cq), 131.5 (CH), 132.1
(Cq), 132.8 (CH), 133.9 (Cq), 135.9 (Cq). The analytical data
obtained are in agreement with those reported in ref 17.
4′-Chloro-5-cyanobiphenyl-2-amine (26). Compound 26 was
prepared from 4-aminobenzonitrile (2.36 g, 20.0 mmol) and 4-
chlorophenylhydrazine hydrochloride (179 mg, 1.00 mmol) according
to the general procedure at 90 °C. The excess of 4-aminobenzonitrile
was removed by Kugelrohr distillation in vacuo at 130 °C. Purification
by column chromatography gave 26 (61.0 mg, 0.27 mmol, 27%): red
oil; Rf = 0.7 (hexane/EtOAc = 4:1) (UV); 1H NMR (600 MHz,
CDCl3) δ 6.74 (d, J = 8.4 Hz, 1 H), 7.33−7.37 (m, 3 H), 7.42 (dd, J =
2.0 Hz, J = 8.4 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 2 H); 13C NMR (91
MHz, CDCl3) δ 100.7 (Cq), 115.4 (CH), 119.5 (Cq), 126.1 (Cq),
129.0 (2 × CH), 130.4 (2 × CH), 132.9 (CH), 134.2 (Cq), 134.4
(CH), 135.5 (Cq), 147.6 (Cq). The analytical data obtained are in
agreement with those reported in ref 17.
1
= 0.7 (hexane/EtOAc = 4:1) (UV); H NMR (600 MHz, CDCl3) δ
3.76 (s, 3 H), 6.89 (dd, JHF = 4.9 Hz, J = 8.7 Hz, 1 H), 6.97−7.03 (m,
2 H), 7.37 (d, J = 8.8 Hz, 2 H), 7.44 (d, J = 8.8 Hz, 2 H); 13C NMR
(151 MHz, CDCl3) δ 56.2 (CH3), 112.4 (d, JCF = 8.3 Hz, CH), 114.6
(d, JCF = 22.6 Hz, CH), 117.2 (d, JCF = 23.5 Hz, CH), 128.3 (2 ×
CH), 128.6 (Cq), 130.7 (2 × CH), 133.4 (Cq), 135.8 (d, JCF = 1.6 Hz,
Cq), 152.5 (d, JCF = 8.1 Hz, Cq), 157.3 (d, JCF = 240.4 Hz Cq); MS
(EI) m/z 238 (30) [37Cl-M+], 237 (14), 236 (100) [35Cl-M+], 221
(19), 186 (98), 157 (24); HRMS (EI) calcd for C13H1035ClFO [M+]
236.0404, found 236.0404. 4′-Chloro-6-fluoro-3-methoxybiphenyl
1
(30′): Rf = 0.3 (hexane/EtOAc = 4:1) (UV); H NMR (600 MHz,
CDCl3) δ 3.79 (s, 3 H), 6.78 (d, JHF = 4.9 Hz, 1 H), 6.82 (dd, JHF = 4.0
Hz, J = 8.8 Hz, 1 H), 6.89 (dd, JHF = 8.8 Hz, 1 H), 7.41−7.48 (m, 4
H); 13C NMR (151 MHz, CDCl3) δ 55.8 (CH3), 114.8 (Cq), 115.3 (d,
JCF = 8.0 Hz, CH), 116.8 (d, JCF = 23.5 Hz, CH), 120.4 (d, JCF = 7.9
Hz, CH), 129.2 (2 × CH), 130.4 (2 × CH), 133.9 (Cq), 135.7 (d, JCF
= 1.6 Hz, Cq), 146.3 (d, JCF = 20.2 Hz, Cq), 153.8 (d, JCF = 240.4 Hz,
Cq); MS (EI) m/z 237 (8), 236 (14), 235 (4), 234 (9), 199 (5), 193
(7), 163 (9), 137 (6), 127 (5), 117 (5), 76 (6), 57 (4), 53 (6), 43 (4),
27 (6), 18 (100); HRMS (EI) calcd for C13H10ClFO [M+] 236.0404,
found 236.0405.
Experiment on a Larger Scale: 4′-Chlorobiphenyl-2-amine (23).
Compound 23 was prepared from aniline (37.2 mL, 400 mmol) and 4-
chlorophenylhydrazine hydrochloride (3.58 g, 20.0 mmol) in the
presence of aqueous sodium hydroxide (1M, 20.0 mL) according to
the general procedure at 60 °C. After phase separation and 3-fold
extraction of the aqueous phase with CH2Cl2 (3 × 20 mL), the excess
of aniline could be recovered in high purity by distillation in vacuo at
80 °C. Purification by column chromatography gave 23 (1.72 g, 8.48
mmol, 43%) and 23′ (357 mg, 1.76 mmol, 9%). The analytical data
obtained are in agreement with those reported in ref 17.
4′-Chloro-5-methoxybiphenyl-2-amine (27). Compound 27 was
prepared from 4-methoxyaniline (2.46 g, 20.0 mmol) and 4-
chlorophenylhydrazine hydrochloride (179 mg, 1.00 mmol) according
to the general procedure at 60 °C. The excess of 4-methoxyaniline was
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The Journal of Organic Chemistry
Note
Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (d) Lersch, M.; Tilset, M.
Chem. Rev. 2005, 105, 2471.
ASSOCIATED CONTENT
■
S
* Supporting Information
(11) For recent articles on C−H activation, see: (a) Ishikawa, A.;
Nakao, Y.; Sato, H.; Sakaki, S. Dalton Trans. 2010, 39, 3279. (b) Foley,
N. A.; Ke, Z.; Gunnoe, T. B.; Cundari, T. R.; Petersen, J. L.
Organometallics 2008, 27, 3007. (c) Ciana, C.-L.; Phipps, R. J.; Brandt,
J. R.; Meyer, F.-M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 458.
(d) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M.
R., III. Science 2002, 295, 305. (e) Chen, X.; Hao, X.-S.; Goodhue, C.
E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (f) Phipps, R. J.;
Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
1H and 13C NMR spectra for all 2-aminobiphenyls 3 and 17−
28 and biphenyl ethers 30 and 30′. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: markus.heinrich@fau.de.
́
(g) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (h) Vallee, F.;
Notes
Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 1514.
(i) Liu, W.; Cao, H.; Lei, A. Angew. Chem., Int. Ed. 2010, 49, 2004.
(j) Pirali, T.; Zhang, F.; Miller, A. H.; Head, J. L.; McAusland, D.;
Greaney, M. F. Angew. Chem., Int. Ed. 2012, 51, 1006.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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We thank Dr. Gotz and Dr. Zierke (Crop Protection, BASF SE,
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Ludwigshafen) for helpful discussions. The financial support of
H.J. by the Graduate School of Molecular Science and the
Deutsche Forschungsgemeinschaft (DFG) is gratefully ac-
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