CoPc-catalyzed selective radical arylation of anilines with arylhydrazines for synthesis of 2-aminobiaryls

Article abstract of DOI:10.1039/c4ob00798k

CoPc-catalyzed selective radical arylation of anilines with arylhydrazines to afford 2-aminobiaryls in moderate to good yields is described. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00798k

Organic &
Biomolecular Chemistry
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CoPc-catalyzed selective radical arylation of
anilines with arylhydrazines for synthesis of
2-aminobiaryls†
Cite this: Org. Biomol. Chem., 2014,
12, 6922
Tao Jiang,a Sheng-Yan Chen,a Guo-Yu Zhang,a Run-Sheng Zenga and
Jian-Ping Zou*a,b
Received 17th April 2014,
Accepted 10th July 2014
DOI: 10.1039/c4ob00798k
CoPc-catalyzed selective radical arylation of anilines with arylhydrazines to afford 2-aminobiaryls in
www.rsc.org/obc
moderate to good yields is described.
Biaryls have attracted considerable attention in chemical Taniguchi group developed a K4[Fe(CN)6]-catalyzed reaction of
sciences because of their applications in organic synthesis, arylhydrazines and alkenes to give oxyarylation products.8
pharmaceuticals and materials.1 A well-known method for syn- More recently, Jiao and co-workers disclosed that the reaction
thesis of biaryls is the Gomberg–Bachmann reaction (first of arylhydrazines and alkenes could yield different products
reported in 1924) using aryldiazonium salts by homolytic aro- depending on the choice of catalyst.9 Manganese(III) acetate
matic substitution.2 Since then, many improvements in this has also been shown to promote the arylation of arenes,
reaction have been explored. Importantly, in the past few heteroarenes and C60 using arylhydrazines through a radical
decades, transition-metal promoted or catalyzed cross-coup- process to afford (hetero)biaryls and functionalized C60.10–12
ling reactions have been discovered, which provide powerful More recently, Heinrich and co-workers reported the reaction
tools for synthesis of biaryls.3 Along with the rapid progress in of arylhydrazines and anilines to afford 2-aminobiaryls in the
transition-metal catalyzed cross-couplings, catalyst controlled presence of MnO2.13 2-Aminobiaryls are key intermediates for
radical initiations and their subsequent reactions have gained synthesis of bestselling fungicides such as Boscalid, Xemium
increasing interest since the 1980s.4 As radical reactions play a and Fontelis (Fig. 1).14 Hence, developing new efficient cata-
more important role in modern organic synthesis, the develop- lytic and selective methods for the synthesis of 2-aminobiaryls
ment and use of a highly efficient transition-metal catalyzed is an important goal for both academia and industry.
system has become a valuable field of research.5
In connection to our research on transition metal-catalyzed
Arylhydrazines are good radical precursors, as they are and/or promoted radical reactions,15 this paper presents a
easily oxidized by air (O2) and various other oxidants to yield novel CoPc-catalyzed,16 regioselective radical arylation of ani-
aryldiazenes (aryldiimides). Aryldiazenes can decompose to lines with arylhydrazines. The initial feasibility studies were
generate aryl radicals, which can then be reacted with arenes performed using phenylhydrazine in benzene with a substoi-
to afford biaryls. The properties, reactivity and mechanisms of chiometric quantity of transition metal salts in air; conse-
aryl radicals derived from arylhydrazines have been extensively quently, CoPc was selected as the catalyst for further reaction
investigated. However, until early 1980s arylhydrazines were exploration.
not suitable substrates for synthesis of biaryls due to their
Initial feasibility studies were performed using phenyl-
poor reaction selectivities, low yields and non-catalytic pro- hydrazine in benzene with a substoichiometric quantity of
cesses.6 In 1989 the Asensio group reported the reaction of transition metal salts in air (Table 1). Reactions were per-
arylhydrazines with alkenes promoted by excess copper(II) salts formed in the presence of different catalysts such as CoCl2,
to afford the arylation products of alkenes.7 Later, the
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and
Chemical Engineering, Soochow University, 199 Renai Street, Suzhou, Jiangsu
215123, China. E-mail: jpzou@suda.edu.cn
bKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Science, 345 Lingling Road, Shanghai
200032, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00798k
Fig. 1 Structure of fungicides Boscalid, Xemium and Fontelis.
6922 | Org. Biomol. Chem., 2014, 12, 6922–6926
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Table 1 Catalyst screeninga
With an initial promising result in hand, we applied these
reaction conditions to the synthesis of 2-aminobiphenyl from
phenylhydrazine and aniline. After screening the reaction
solvent, temperature, time and catalyst loading (Table 3,
entries 1–12), optimal reaction conditions were identified: the
reaction of phenylhydrazine (1.0 equiv.) and aniline (10 equiv.)
was carried out in the presence of CoPc (10 mol%) in CH3CN
at 80 °C for 24 h (Table 3, entry 9), which afforded 2-amino-
biphenyl in 62% yield.
The optimal reaction conditions were then employed for
the reaction of a variety of substituted anilines. Anilines with
para-electron-withdrawing groups such as F, Cl, Br, NO2 and
CN were all tolerated, although a slight drop in yield was
noted for 3c–f (50–55%, Table 4, entries 2–6). In comparison,
anilines with para-electron-donating groups such as CH3, OH,
OCH3 and NH2 showed a marked improvement in the reaction
yield, producing the expected biaryl products in good yields
(Table 4, entries 7–11). In most cases, the expected 2-amino-
biaryls were generated as the sole products although somewhat
surprisingly 4-cyanoaniline yielded a mixture of two isomeric
products in a 1 : 1 ratio (Table 4, entry 6). To assess the effect
of substitution pattern on the regioselectivity of the reaction,
anilines with ortho- (CH3, OH, NO2) and meta- (OH and NO2)
substituents were subjected to the reaction conditions
(Table 4, entries 12–16). The anilines bearing ortho- and meta-
electron-donating substituents all gave biaryl products in good
yields. Unfortunately, these reactions were not regioselective,
generating isomeric mixtures (Table 4, entries 12, 13 and 15).
In contrast, anilines with ortho- and meta-electron-withdrawing
groups afforded single products 3l (45%) and 3n (57%),
respectively (Table 4, entries 14 and 16). The results in Table 4
indicate that the phenyl radical generated from phenylhydra-
zine is electrophilic in nature, hence radical acceptors with
high electron density are favored in the arylation reaction.
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
9
—
CoCl2
Co(OAc)2
Co(acac)3
FePc
CoPc
CuPc
MnTppCl
FeTppCl
CoTppCl
N.D.c
8
10
11
40
43
37
20
25
28
10
a Reaction conditions: phenylhydrazine (1.0 mmol), benzene (5 mL)
and catalyst (10 mol%) at reflux for 24 h in air. b Isolated yields. c The
reaction was performed without a catalyst in air. N.D. means not
detected.
Co(OAc)2 and Co(acac)2, the expected product biphenyl was
obtained albeit in low yields (Table 1, entries 2–4). In the
absence of a catalyst no desired product was observed (Table 1,
entry 1). We then turned our attention to the use of phthalo-
cyanine metal complexes MPc (M = Fe, Co, Cu), and to our
delight, the reaction yields were greatly improved (Table 1,
entries 5–7). Using CoPc as the catalyst delivered the desired
product in the best yield (43%, Table 1, entry 6). Furthermore,
utilization of the related tetraphenylporphyrin metal com-
plexes MTppCl (M = Mn, Fe, Co) for the same reaction gave the
products in 20–28% yields (Table 1, entries 8–10). Conse-
quently, CoPc was selected as the catalyst for further reaction
exploration. To understand the substrate scope, some substi-
tuted benzenes such as toluene, phenol, chlorobenzene and
aniline were used for the reaction, the results indicated that
aniline is a better substrate (Table 2, entry 4).
Table 3 Optimization of the reaction conditionsa
T
(°C)
Time
(h)
Aniline
(equiv.)
CoPc
(mol%)
Yieldb
(%)
Entry
Solvent
Table 2 Substrate screeninga
1
2
3
4
5
6
7
8
CH3CN
THF
DMSO
AcOH
80
80
80
80
80
80
25
80
80
80
80
80
24
24
24
24
24
24
24
12
24
24
24
24
20
20
20
20
20
20
20
20
10
5
10
10
10
10
10
10
10
10
10
10
20
5
62c
50
N.D.d
N.D.d
N.D.d
N.D.d
20
DMF
CH3NO2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
T
Time
CoPc
(mol%) (%)
Yieldb
Entry Solvent (°C) (h)
Substrate (equiv.)
45
9
62e
1
2
3
4
CH3CN 80
CH3CN 80
CH3CN 80
CH3CN 80
24
24
24
24
Toluene (20)
Phenol (20)
10
10
Trace
10
11
12
38
62
48
Trace
Trace
62c
10
20
Chlorobenzene (20) 10
Aniline (20) 10
a Using phenylhydrazine (1.0 mmol) and 10 mL solvent for all the
reactions. b Isolated yield. c Mixture of 2-amino- and 4-aminobiphenyl
(3 : 1), analyzed by GC. d Not detected. e No 4-aminobiphenyl was
isolated.
a Using phenylhydrazine (1.0 mmol) and 10 mL CH3CN as a solvent for
all the reactions. b Isolated yield. c Mixture of 2-amino- and
4-aminobiphenyl (3 : 1), analyzed by GC.
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Table 4 Coupling reactions of phenylhydrazine (1a) with anilines (2)a
Subsequently, the effect of substitution on arylhydrazines
was probed (Table 5). In general, both the electron-donating
group (CH3) and the electron-withdrawing group (F, Cl and Br)
at the para-position of the arylhydrazine afforded the expected
products in good yields (Table 5, entries 1, 3, 4, 5, 11 and 12).
However, 4-methoxyphenyl-hydrazine gave only a trace amount
of the corresponding biaryl 3p (Table 5, entry 2), the reason
remained unknown. The reactions of para-methyl- and meta-
methyl-phenylhydrazine with 2i afforded the corresponding
2-aminobiaryl products in 76% and 70% yield, respectively
(Table 5, entries 1 and 12). The ortho-methylphenyl-hydrazine
on the other hand, led to only a trace amount of the expected
product (Table 5, entry 10). It is likely that the ortho-substi-
tuent in this case has blocked the reaction of the ortho-methyl-
phenyl radical with 2i. In the cases where arylhydrazines
Entry Aniline
1
Product
Yieldb (%)
3a (62)
2
3
4
5
6
3b (61)
3c (55)
3d (53)
Table 5 Coupling reactions of arylhydrazines (1) with p-anisidine (2i)a
3e (50)
3f : 3f′ = 1 : 1 (50)
Entry
1
R1
H
R2
Product
Yieldb (%)
7
8
3g (70)
3h (74)
4-Me
3o (76)
2
3
4
5
6
H
H
H
H
H
4-OMe
4-Cl
3p (trace)c
31 (77)
9
3i (77)
3j (79)
4-Br
3r (78)
10
4-F
3s (80)
4-CN
3t (trace)c
11
3k (73)
7
8
9
H
4-COOMe
4-NO2
85
90d
88
12
13
65c
70c
H
NO2
4-NO2
10
11
12
13
CH3
H
H
3u (trace)c
3v (73)
14
15
3l (45)
3-Cl
3-Me
3m (70)c
H
3w (73)
Tracec
16
3n (57)
a Reaction conditions: 1a (1.0 mmol), 2 (10 equiv.) and 10 mol% CoPc
in CH3CN (10 mL) at 80 °C for 24 h in air. b Isolated yields. c Total yield
of the mixtures.
a Reaction conditions: 1 (1.0 mmol), 2 (10 equiv.) and 10 mol% CoPc
in CH3CN (10 mL) at 80 °C for 24 h in air. b Isolated yield. c Analyzed
by LC-MS. d 2-Nitrophenylhydrazine also gave nitrobenzene in 85%
yield.
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methodology provides a green and cost-effective method for
the efficient preparation of 2-aminobiaryls.
Acknowledgements
JPZ thanks the National Natural Science Foundation of China
for financial support (no. 20772088, 21172163) and a project
funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions.
Scheme 1 Proposed mechanism.
Notes and references
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NO2), the aryl radical addition to 4-methoxyaniline (2i) did not
proceed (Table 5, entries 6–9). Instead, the generated radical
had abstracted a hydrogen to form the corresponding arene,
the strong electron-withdrawing group may render the aryl
radical too reactive to allow the desired process with aniline to
proceed. Finally, an alkylhydrazine, tert-butylhydrazine hydro-
chloride, was applied to the reaction but only a trace amount
of the expected product was detected (Table 5, entry 13),
demonstrating that alkylhydrazines are not suitable precursors
for alkyl radical in this process.
A plausible mechanism for the CoPc-catalyzed coupling of
arylhydrazines and arylamines is proposed in Scheme 1. The
arylhydrazines (1) can be oxidized by CoPc to form aryldia-
zenes (5) through consecutive oxidations via an intermediate
arylhydrazyl radical (4). Aryldiazenes (5) are easily oxidized to
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(8), allowing 2-aminobiaryls (3) to be formed by oxidation and
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In conclusion, a new CoPc-catalyzed method for synthesis of
2-aminobiaryls was developed for the reaction of arylhydra-
zines and anilines. The reaction proceeded under mild con-
ditions in air to afford 2-aminobiaryls in up to 80% yield. As
this reaction proceeds through
a metal-catalyzed radical
process utilizing oxygen as the terminal oxidant, there is no
need to add oxidants and additives. A number of 2-aminobiar-
yls have been synthesized using the developed methodology,
most with exquisite selectivity. 2-Aminobiaryls are key inter-
mediates for the synthesis of fungicides, such as Boscalid,
Xemium and Fontelis (Trade name), as well as building blocks
for liquid crystals, organic electronic devices and conductors,
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