Air-promoted direct radical arylation of anilines with arylhydrazines

Article abstract of DOI:10.1016/j.tetlet.2014.06.099

Air-promoted coupling reaction of arylhydrazines and arylamines is developed for the selective synthesis of 2-aminobiaryls. This protocol provides a green, cost-effective, and scale-up method for preparation of 2-aminobiaryls.

Full text of DOI:10.1016/j.tetlet.2014.06.099

Accepted Manuscript
Air-promoted direct radical arylation of anilines with arylhydrazines
Tao Jiang, Sheng-Yan Chen, Huan Zhuang, Run-Sheng Zeng, Jian-Ping Zou
PII:
S0040-4039(14)01112-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.06.099
TETL 44824
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 March 2014
12 June 2014
26 June 2014
Please cite this article as: Jiang, T., Chen, S-Y., Zhuang, H., Zeng, R-S., Zou, J-P., Air-promoted direct radical
arylation of anilines with arylhydrazines, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.06.099
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Air-promoted direct radical arylation of anilines with Leave this area blank for abstract info.
arylhydrazines
Tao Jiang,a Sheng-Yan Chen, a Huan Zhuang, a Run-Sheng Zeng, *a Jian-Ping Zou*a, b

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lsevier .com
Air-promoted direct radical arylation of anilines with arylhydrazines
Tao Jiang,a Sheng-Yan Chen, a Huan Zhuang, a Run-Sheng Zeng, *a Jian-Ping Zou*a, b
a Key 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
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Air-promoted coupling reaction of arylhydrazines and arylamines is developed for the selective
synthesis of 2-aminobiaryls. This protocol provides a green, cost-effective and scale-up method
for preparation of 2-aminobiaryls.
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords
radical reaction
arylhydrazine
2-aminobiaryl
air oxidation
Biaryl is core structure of many fuctional compounds,
medicines and materials, 1 so they have attracted considerable
attention. Gomberg−Bachmann reaction is a well-known
method for synthesis of biaryls, it was first reported in 1924, 2
so far, the reaction conditions had been much improved.
During the past decades, a lot of new cross-coupling reactions
catalyzed or promoted by transition-metal were discovered,
which provided the powerful tools for synthesis of biaryls. 3
Along with the rapid development of the transition-metal
catalyzed reaction, controllable radical reactions have gained
increasing interests since 1980’s, many novel radical process
2-Aminobiaryls are key intermediates for synthesis of best-
selling fugicides such as Xemium, Boscalid and other
9
funtional compounds,
so developing metal-free, cost-
effective and scale-up method for synthesis of 2-aminobiaryls
are significant both in academia and industry. In connection
10
to our research on selective radical reactions,
herein, we
report an air-promoted direct radical arylation of anilines with
arylhydrazines to afford 2-aminobiaryls, this reaction
proceeds in aqueous sodium hydroxide solution, with no need
of oxidants.
10c
In our previous paper,
the copper-catalyzed coupling
4
were disclosed, the radical reactions play more important
role in current organic synthesis. 5
reaction of arylhydrazines and trialkylphosphites was
described, in which CuO and base are crucial for C-P bond
formation. We consider whether C-C bond can be formed in
the absence of a metal catalyst. In the initial experiment, the
reaction of 4-chlorophenylhydrazine and benzene was
selected as model, which gave the expected 4-chlorobiphenyl
in 11% yield (Table 1, entry 1). Then, phenol, anisole, aniline
and 4-chloroaniline were employed for the reaction, 4-
chloroaniline gave the selective 2-amino-4’-chlorobiphenyl in
73% yield (Table 1, entries 2-5). It is worthy to note that 10
equivalent of 4-chloroaniline is necessary to trap 4-
chlorophenyl radical intermediate completely. After base,
solvent and time screening (Table 1, entries 6-19), the optimal
reaction conditions were determined to be: the reaction of 4-
chlorophenylhydrazine and 4-chloroaniline carried out in the
presence of 6 equivalent of NaOH in CH3CN/H2O(3:2) at 80
oC for 3h in air (Table 1, entry 18).
Arylhydrazines are easily oxidized by various oxidants to
yield aryldiazene (aryldiimide), then aryl radicals, which react
with arenes to afford biaryls. Although the properties,
reactions and mechanisms of aryl radicals derived from
arylhydrazines had been much investigated, however,
arylhydrazine did not become a good substrate for synthesis
of biaryls because of diverse products and lower yield until
early 1980's. 6 Afterwards, several transition-metal promoted
or catalyzed reactions of arylhydrazines and alkenes, arenes,
heteroarenes and C60 were reported,7 however, metal-free
reaction is less explored. 8
The above optimal conditions were applied for the reaction
of phenylhydrazine and aniline derivatives. The results in
Table 2 showed that phenyl radical facilitated the attack of

2
Tetrahedron
Table 1. Optimization of the reaction conditionsa
Table 2. Coupling reactions of phenylhydrazine (1a)
with para-substituted anilines (2) a
H2O
(mL)
Time
(h)
Solvent
(3mL)
Yieldb
(%)
Base
Substrate
Entry
1
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
Benzene
2
2
2
2
2
2
2
2
2
3
1
2
2
2
2
2
2
2
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
1
3
10
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
EtOH
11
Trace
Trace
41
2
Phenol
3
Anisole
4
Aniline
5
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
4-ClC6H4NH2
73
6
53
7
t-BuOK
Cs2CO3
n-Bu4NOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
45
8
61
9
39
10
11
12
13
14
15
16
17
18
42
64
23
32
THF
43
DMSO
DMF
17
25
CH3CN
CH3CN
CH3CN
21
72
19
73
a
Reaction conditions: 4-chlorophenylhydrazine (1.0 mmol), substrate
o
(10.0 mmol), base (6.0 mmol) and H2O (2 mL) in CH3CN (3.0 mL) at 80 C
for 3h in air. b Isolated yield.
a Reaction conditions: 1a (1.0 mmol), 2 (10.0 mmol), NaOH (6.0 mmol)
the site with high electron density, so aniline gave the 2-
aminobiaryl as major product in 45% yield and minor 4-
aminobiaryl was observed but not isolated. Therefore, anilines
bearing para-substituted electron-withdrawing groups such as
F, Cl and Br afforded the 2-aminobiaryls in high yields (Table
2, entries 2-4) except 4-nitroaniline (Table 2, entry 5), but
anilines bearing para-substituted electron-donating groups
such as CH3, OCH3 lowered the yield slightly (Table 2,
entries 6-7).
b
and H2O (2 mL) in CH3CN (3.0 mL) at 80 oC for 3h in air. Isolated
yield.
disappointedly, no reaction was observed.
A plausible mechanism for the air-promoted selective
coupling reaction of arylhydrazines and arylamines is
proposed in Scheme 1. Arylhydrazines (1) are oxidized by air
(O2) to form arylhydrazyl radicals (5), followed by release of
N2 to yield aryl radicals (6), which are selectively added to the
ortho-position of anilines (2) to produce radical (7), 2-
aminobiaryls (3) are formed by rearomatization of 7.
Subsequently, the scope of arylhydrazines was investigated.
As seen in the Table 3, arylhydrazines with electron-withdrawing
groups such as F, Cl and Br favored the reaction and afforded the
expected product, 2-aminobiaryls in good yields (Table 3, entries
1-3), but 4-nitrophenylhydrazine gave a trace amount of product
(Table 3, entry 4) and no reaction was observed for the 3-chloro-
5-trifluoromethylphenylhydrazine (Table 3, entry 5). On the
contrary, arylhydrazines with electron-donating groups such as
CH3, isopropyl, t-butyl and OCH3 reduced the yield (Table 3,
entries 6-11). The reactions of p-methyl- and m,m-
dimethylphenylhydrazines with 4-chloroaniline afforded the
corresponding aminobiaryls in 51% and 48% yields, respectively
(Table 3, entries 6 and 7), compared to the o-methyl- and o-
ethylphenylhydrazines which afforded the corresponding
products in 35% and 31% yields, respectively (Table 3, entries 12
and 13). It is worthy to note the steric effect of ortho-substituent
on arylhydrazine. To know the scope and limitations of this
methodology, the reaction was extended to the t-butylhydrazine,
phenylsulfonyl hydrazine and benzoylhydrazine,
Scheme 1 Mechanism for the reaction of arylhydrazines and arylamines

3
Table 3. Coupling reactions of arylhydrazines (1) with
4-chloroaniline (2c) a
In conclusion, a novel air-promoted method for selective
synthesis of 2-aminobiaryls was developed from the coupling
reaction of arylhydrazines and arylamines. The reaction
proceeded under mild conditions in aqueous sodium
hydroxide solution to afford 2-aminobiaryls in moderate to
good yields. 2-Aminobiaryls are key intermediates for the
synthesis of fungicides such as Xemium and Boscalid, also
they are used as building blocks for dyes, liquid crystals,
organic devices and conductors, ligands for metal catalysts
and medicines. This protocol provides a green, cost-effective
and scale-up method for preparation of 2-aminobiaryls.
Acknowledgments
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.
Notes and references
1
(a) K. Narasaka, Synthesis, 1991, 1; (b) G. Bringmann, R. Walter and R.
Weirich, Angew. Chem., 1990, 102, 1006; Angew. Chem. Int. Ed. Engl.,
1990, 29, 977; (c) R. Noyori, Chem. Soc. Rev., 1989, 18, 187; (d) I.
Cepanec, Synthesis of Biaryls, Elsevier, New York, 2004; (e) G. M.
Keserffl and M. Nhgridi, Studies in Natural Products Chemistry, Vol.
20 (Ed.: Atta-ur-Rahman), Elsevier, Amsterdam, 1998, p. 263.
2
3
M. Gomberg and W. E. Bachmann, J. Am. Chem. Soc., 1924, 46, 2339.
(a) H. Bonin, E. Fouquet and F. X. Felpin, Adv. Synth. Catal., 2011, 353,
3063; (b) P. Lloyd-Williams and E. Giralt, Chem. Soc. Rev., 2001, 30,
145; (c) S. P. Stanforth, Tetrahedron, 1998, 54, 263; (d) G. Bringman, R.
Walter and R. Weirich, Angew. Chem. Int. Ed. Engl., 1990, 29, 977; (e)
M. Sainsbury, Tetrahedron, 1980, 36, 3327.
4
(a) W. C. Trogler, Organometallic Radical Processes, Elsevier,
Amsterdam, 1990, Chap. 3, 4, 9, 10; (b) D. Astruc, Electron Transfer
and Radical Processes in Transition-Metal Chemistry, VCH, New York,
1995, Chap. 3, 5, 6; (c) D. Astruc, Acc. Chem. Res., 1991, 24, 36; (d) K.
E. Torraca and L. McElwee-White, Coord. Chem. Rev., 2000, 206 - 207,
469; (e) J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev.,
2011, 40, 102; (f) C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012,
41, 3464;
5
(a) C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem. Rev.,
1999, 99, 1991; (b) A. Gansauer and H. Bluhm, Chem. Rev., 2000, 100,
2771; (c) M. P. Sibi, S. Manyem and J. Zimmerman, Chem. Rev., 2003,
103, 3263; (d) T. R. Rheault and M. P. Sibi, Synthesis, 2003, 803; (e)
Radicals in Synthesis I and II, Vols. 263 – 264 of Topics in Current
Chemistry (Ed.: A. Gansauer), Springer, Berlin, 2006; (f) Radicals in
Organic Synthesis: Formation of Carbon-Carbon Bonds (Ed.: B. Giese),
Pergamon, Oxford, 1986; (g) Stereochemistry of Radical Reactions (Eds.:
D. P. Curran, N. A. Porter, B. Giese), Wiley-VCH, Weinheim, 1996; (h)
Radicals in Organic Synthesis (Eds.: P. Renaud, M. P. Sibi), Wiley-VCH,
Weinheim, 2001.
6
7
8
(a) H. A. O. Hill and P. J. Thornalley, FEBS Lett., 1981, 125, 235; (b) J.
B. Aylward, J. Chem. Soc. B, 1969, 1663; (c) E. M. Kosower, P. C.
Huang and T. Tsuji, J. Am. Chem. Soc., 1969, 91, 2325; (d) P. C. Huang
and E. M. Kosower, J. Am. Chem. Soc., 1968, 90, 2367; (e) E. S. Huyser
and R. H. S. Wang, J. Org. Chem., 1968, 33, 3901; (f) F. L. Scott and J.
A. Barry, Tetrahedron Lett., 1968, 9, 2461; (g) R. L. Hardie and R. H.
Thomson, J. Chem. Soc., 1957, 2512; (h) F. D. Chattaway, J. Chem. Soc.
Trans., 1907, 91, 1323; (i) Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds., B. Giese, Ed. Pergamon Press, 1986, 241-247;
(a) T. Varea, M. E. González-Núñez, J. Rodrigo-Chiner and G. Asensio,
Tetrahedron Lett., 1989, 30, 4709; (b) T. Taniguchi, H. Zaimoku and H.
Ishibashi, Chem. Eur. J., 2011, 17, 4307; (c) A. S. Demir, Ö. Reis and E.
Özgül-Karaaslan, J. Chem. Soc. Perkin Trans. 1, 2001, 3042; (d) A. S.
Demir, Ö. Reis and M. Emrullahoglu, Tetrahedron, 2002, 58, 8055; (e)
Z.-X. Chen and G.-W. Wang, J. Org. Chem., 2005, 70, 2380; (f) G.-W.
Wang, Y.-M. Lu and Z.-X. Chen, Org. Lett., 2009, 11, 1507; (g) H.
Jasch, J. Scheumann and M. R. Heinrich, J. Org. Chem., 2012, 77,
10699.
a Reaction conditions: hydrazine (1.0 mmol), 2c (10.0 mmol), NaOH (6.0
o
mmol) and H2O (2 mL) in CH3CN (3.0 mL) at 80 C for 3h in air. b Isolated
yield.
Y. Su, X. Sun, G. Wu and N Jiao, Angew. Chem. Int. Ed., 2013, 52, 9808.

4
Tetrahedron
9
(a) K. Eicken, H. Rang, A. Harreus, N. Goetz, E. Ammermann, G.
10 (a) X.-Q. Pan, J.-P. Zou, L. Wang and W. Zhang, Chem. Commun., 2010,
46, 1721; (b) X.-Q. Pan, L. Wang, J.-P. Zou and W. Zhang, Chem.
Commun., 2011, 47, 7875; (c) S.-Y. Chen, R.-S. Zeng, J.-P. Zou and O.
T. Asekun, J. Org. Chem., 2014, 79, 1449; (d) D.-P. Li, X.-Q. Pan, L.-T.
An, J.-P. Zou and W. Zhang, J. Org. Chem., 2014, 79, 1850; (e) X.-H.
Cao, X.-Q. Pan, P.-J. Zhou, J.-P. Zou and O. T. Asekun, Chem.
Commun., 2014, 50, 3359.
Lorenz and S. Strathmann, DE19531813, 1997; (b) K. Eicken, M. Rack,
F. Wetterich, E. Ammermann, G. Lorenz and S. Strathmann, DE
19735224, 1999; (c) E. Berner, R. Milling, R. E. Gold and R. Stierl,
WO2007054473; (d) R. Stierl, J. Dietz, B. Muller, M. Scherer, S.
Strathmann, F. Werner and M. Vonend, EP1813151; (e) W. Jo
̈rges, J.-D.
Heinrich and R. B. C. Lantzsch, WO2006024388.