One-pot synthesis of diarylamines from two aromatic amines via oxidative dearomatization-imino exchange-reductive aromatization

Article abstract of DOI:10.1021/ol4007162

A one-pot synthetic strategy for diarylamines using only aromatic amines as starting materials has been developed. This method involved a PhI(OAc) ₂-induced oxidative dearomatization of N-sulfonyl protected para-substituted anilines, a Bi(OTf)₃-catalyzed imino exchange reaction between N-sulfonyl cyclohexadienimines and aromatic amines, and a CF₃COOH/Zn mediated reductive aromatization of the resulting N-aryl cyclohexadienimines.

Full text of DOI:10.1021/ol4007162

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2018–2021
One-Pot Synthesis of Diarylamines
from Two Aromatic Amines via
Oxidative DearomatizationÀImino
ExchangeÀReductive Aromatization
Li Zhang,† Weibin Wang,*,‡ and Renhua Fan*,†
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433,
China, and Department of General Surgery, Peking Union Medical College Hospital,
Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuai Fu
Yuan, Dongcheng District, Beijing, 100730, China
rhfan@fudan.edu.cn; wwb_xh@yahoo.com.cn
Received March 18, 2013
ABSTRACT
A one-pot synthetic strategy for diarylamines using only aromatic amines as starting materials has been developed. This method involved a PhI(OAc)2-
induced oxidative dearomatization of N-sulfonyl protected para-substituted anilines, a Bi(OTf)3-catalyzed imino exchange reaction between N-sulfonyl
cyclohexadienimines and aromatic amines, and a CF3COOH/Zn mediated reductive aromatization of the resulting N-aryl cyclohexadienimines.
Diarylamines constitute a valuable class of compounds
in biological, pharmaceutical, and material sciences.1 They
not only are found in a variety of natural products,
agrochemicals, and HIV-1 protease inhibitors but also
are widely used as corrosion inhibitors, antioxidants and
stabilizers for rubber, and additives for the production of
dyes. The classical approach to prepare diarylamines2 is the
transition-metal catalyzed N-arylation of aromatic amines,
such as the Ullmann reaction3À5 and the BuchwaldÀ
Hartwig amination.6,7 Recently, Larock and co-workers
reported a transition-metal-free N-arylation procedure with
arynes as a reactive intermediate.8 The Deng group devel-
oped a palladium-catalyzed diarylamine formation from
nitroarenes and cyclohexanones using the dehydrogenation
and borrowing hydrogen methodology.9 The Nakamura
group described an iron-catalyzed amination reaction of
† Fudan University.
‡ Chinese Academy of Medical Science and Peking Union Medical
College.
(1) (a) Lawrence, S. A. Amines: Synthesis Properties and Applications;
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A. V. J. Med. Chem. 2004, 47, 2816. (c) Suwanprasop, S.; Nhujak, T.;
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r
10.1021/ol4007162
Published on Web 04/08/2013
2013 American Chemical Society

aryl bromides with in situ generated magnesium amides to
provide diaryl- and triarylamines without the use of expen-
sive and/or toxic metals.10 Because of the importance of
diarylamines, aside from the reliability of the existing proto-
cols,11,12 the search and development of an alternative
method to construct such a desirable framework by using
only aromatic amines as starting materials is still highly
desirable (Scheme 1).
Scheme 2. One-Pot Synthesis of Diarylamines from Two
Aromatic Amines
As a result of the inherent functionalities stored within
the aromatic systems, dearomatization13 of aromatic amines
provided a powerful tool to build complex nitrogen-
containing molecules.14 The oxidative dearomatization
of para-substituted anilines forms cyclohexadienimines.
The Kerr,15 Quideau,16 and Canesi17 groups have devel-
oped 1,4-additions of cyclohexadienimines to convert these
motifs into useful molecules. In contrast, the 1,2-addition of
cyclohexadienimines has received much less scrutiny. Our
planned one-pot synthetic strategy for diarylamines from
two aromatic amines involved an oxidative dearomatization
of N-sulfonyl protected para-substituted anilines, an imino
exchange between the in situ generated N-sulfonyl cyclohexa-
dienimines and aromatic amines, and a reductive aromatiza-
tion of the resulting N-aryl cyclohexadienimines (Scheme 2).
N-Ts protected p-toluidine in methanol with PhI(OAc)2 as
the oxidant (Table 1). No reaction was observed in the
absence of a catalyst. To promote the 1,2-addition and the
subsequent elimination of TsNH2, various Lewis acids
were examined. Except for Au(PPh3)Cl, a range of metal
salts exhibited catalytic activities in the imino exchange
reaction. Bi(OTf)3 was the best catalyst for the formation
of N-aryl cyclohexadienimine 5aa. More importantly,
Bi(OTf)3 could efficiently promote the imino exchange
reaction in methanol (Table 1, entry 14), which made it
possible to combine the oxidative dearomatization and the
imino exchange reaction into a one-pot procedure.
Scheme 1. Strategies for the Preparation of Diarylamines
We next investigated the reductive aromatization of N-
aryl cyclohexadienimine 5aa in methanol. When NaBH4 was
used as the reductant together with 1 equiv of BF3 Et2O, the
3
reaction was very complex (Table 2, entry 1). Interestingly,
when BF3 Et2O was used alone, the reaction gave rise to the
3
desired diarylamine 6aa in a 34% yield (Table 2, entry 2).
Analysis of the reaction mixture indicated the formation
of benzoquinone. It was supposed that benzoquinone was
formed from the oxidation of 4-methoxybenzenamine,
which was generated from the hydrolysis of N-aryl cyclo-
hexadienimine. Indeed, the addition of 1 equiv of 4-meth-
oxybenzenamine in the BF3 Et2O-catalyzed reaction led to
an improvement in the product yield (Table 2, entry 3).
3
First, we investigated the imino exchange reaction be-
tween 4-methoxybenzenamine and cyclohexadienimine3a,
which was prepared from the oxidative dearomatization of
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Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215. (e) Hamann, B.;
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Org. Lett., Vol. 15, No. 8, 2013
2019

Table 1. Evaluation of Catalyst for Imino Exchange Reactiona
Table 2. Evaluation of Conditions for Reductive Aromatization
6aa (%)a
entry
catalyst
5aa (%)b
entry
catalyst
5aa (%)b
entry
catalyst (equiv)
reductant (equiv)
1
2
3
4
5
6
7
À
0
8
In(OTf)3
Fe(OTf)2
Yb(OTf)3
Sc(OTf)3
Dy(OTf)3
Bi(OTf)3
Bi(OTf)3
44
68
73
93
67
96
95
1
BF3 Et2O (1)
NaBH4 (1)
À
0
3
Au(PPh3)Cl
CuBr
<5
75
90
92
72
91
9
2
BF3 Et2O (1)
34
60
53
56
52
65
27
31
36
<5
36
83
94
3
10
11
12
13
14c
3
BF3 Et2O (1)
4-MeOC6H4NH2 (1)
4-MeOC6H4NH2 (2)
4-MeOC6H4NH2 (1)
4-HOC6H4OH (1)
4-MeOC6H4NH2 (1)
PPh3 (1)
3
AgOTf
4
BF3 Et2O (1)
3
Cu(OTf)2
Zn(OTf)2
Ni(OTf)2
5
BF3 Et2O (2)
3
6
BF3 Et2O (1)
3
7
CF3COOH (1)
CF3COOH (1)
CF3COOH (1)
CF3COOH (1)
CF3COOH (1)
CF3COOH (1)
CF3COOH (1)
CF3COOH (2)
8
a General reaction conditions: reactions performed on 0.2 mmol
scale using 1.1 equiv of 2a, 10 mol % catalyst in t-BuOH (2 mL) at 25 °C,
unless noted. b Reported yields are of the isolated product based on
compound 3a. c MeOH was used as solvent.
9
PBu3 (1)
10
11
12
13
14
H2 (1 atmo)
Sn (1)
Mg (1)
Zn (1)
Increasing the amount of 4-methoxybenzenamine or BF3 Et2O
3
Zn (2)
did not improve the yield (Table 2, entries 4 and 5). Screening
of a variety of Lewis acids or Brønsted acids revealed that
2,2,2-trifluoroacetic acid could also promote the reductive
aromatization in methanol (Table 2, entry 7). Moreover, we
were pleased to find that the yield of the desired product was
improved to 83% by using a combination of 2,2,2-trifluoro-
acetic acid and zinc dust (Table 2, entry 13). When the
amounts of 2,2,2-trifluoroacetic acid and Zn dust were
increased to 2 equiv, the reductive aromatization reaction
afforded diarylamine 6aa in a 94% yield.
a Reported yields are of the isolated product based on compound 5aa.
dearomatization of N-Ts protected p-toluidine in isopro-
panol or tertiary butanol did not form the corresponding
cyclohexadienimines due to the poor nucleophilicity of
these alcohols. When isopropanol or tertiary butanol was
used together with 2 equiv of methanol, the reactions gave
rise to cyclohexadienimine 3a in low yields (<10%).
With the optimized reaction conditions established, the
one-pot synthesis of diarylamines was investigated, and
representative results were shown in Table 3. For various
4-substituted anilines, the reactions proceeded smoothly
leading to the corresponding diarylamines in moderate to
good yields. A steric hindrance effect was observed in the
imino exchange reaction when 2,4-dimethylbenzenamine
1h was used as the substrate (Table 3, entry 8). When N-Ts
protected 4-methoxybenzenamine 1i was used, the oxida-
tive dearomatization proceeded smoothly, but the imino
exchange reaction was very complex (Table 3, entry 9). A
variety of aromatic amines could be used as reaction partners
for this one-pot synthesis. When sterically hindered amines
2eÀg were used as nucleophiles, the desired diarylamines
were still obtained with good yields (Table 3, entries 13À15).
The reaction system displayed good tolerance toward a range
of functional groups. When unprotected aminophenol 2h
or 2i was employed, the reaction afforded the corresponding
N-arylated aminophenol18 6ah or 6ai in a 91 or 83% yield,
respectively (Table 3, entries 16 and 17). In addition, the one-
pot reaction between 2-iodobenzenamine and p-toluidine
Isopropanol and tertiary butanol could also be used as
the medium for the imino exchange reaction and the
reductive aromatization reaction. However, the oxidative
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2020
Org. Lett., Vol. 15, No. 8, 2013

Table 3. One-Pot Synthesis of Diarylamines from Two
Aromatic Amines
Scheme 3. Conversion of 2-Iodo-N-p-tolylbenzenamine 6aj
entry
Ar1
Ar2
4-MeOC6H4
6 (%)a
1
4-MeC6H4
4-nBuC6H4
4-EtC6H4
6aa (83)
6ba (75)
6ca (88)
6da (70)
6ea (45)
6fa (63)
6ga (73)
6ha (35)
6ia (0)
to survive. The reaction of 4-amino-pyridine or 5-amino-1,3-
dimethyl-1H-pyrazole was very complex, and product 6am
or 6an was not isolated (Table 2, entries 21 and 22).
Diarylamine 6aj could be converted to 3-methyl-
9H-carbazole 7 via a palladium-catalyzed intramolecular
direct arylation19 (Scheme 3).
In conclusion, we have developed a new strategy for
accessing diarylamines using only aromatic amines as
starting materials. This one-pot synthesis involves an
oxidative dearomatization, an imino exchange reaction,
and a reductive aromatization. Currently, extending its
scope and exploring its reaction mechanism and possible
synthetic applications are being pursued, and these results
will be reported in due course.
2
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
3
4
4-iPrC6H4
4-MeOC6H4
4-PhC6H4
3,4-(Me)2C6H3
2,4-(Me)2C6H3
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
6ab (76)
6ac (80)
6ad (80)
6ae (98)
6af (73)
6ag (80)
6ah (91)
6ai (83)
6aj (48)
6ak (85)
6al (85)
6am (0)
6an (0)
4-MeC6H4
4-iPrC6H4
2-MeC6H4
2,6-(Me)2C6H3
2,4,6-(Me)3C6H2
4-HOC6H4
2-HOC6H4
2-IC6H4
Acknowledgment. Financial support from National
Natural Science Foundation of China (No. 21072033) is
gratefully acknowledged.
4-FC6H4
1-naphthyl
4-pyridyl
1,3-(CH3)2-1H-pyrazol-5-yl
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Reported yields are of the isolated products based on compounds 1.
generated 2-iodo-N-p-tolylbenzenamine 6aj in a reasonable
yield. Under the transition-metal catalyzed N-arylation
conditions, iodo substitution in aromatic amines is unlikely
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
2021