Transition-Metal-Free Dehydrogenative N–N Coupling of Secondary Amines with KI/KIO4

Article abstract of DOI:10.1002/ejoc.201900763

A transition-metal-free method for the dehydrogenative N–N coupling of secondary amines has been accomplished. This oxidative KI/KIO₄ protocol is mild and operationally simple. A diverse range of diphenylamines, carbazoles, and N-alkylanilines readily undergo N–N homo-coupling effectively. Notably, the N–N cross-coupling of two different arylamines is also demonstrated, which provides a straightforward approach to the complex N–N structures.

Full text of DOI:10.1002/ejoc.201900763

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Accepted Article
Title: Transition-Metal-Free Dehydrogenative N–N Coupling of
Secondary Amines with KI/KIO₄
Authors: Dehang Yin and Jian Jin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900763
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10.1002/ejoc.201900763
European Journal of Organic Chemistry
COMMUNICATION
Transition-Metal-Free Dehydrogenative N–N Coupling of
Secondary Amines with KI/KIO4
Dehang Yin,[a] and Jian Jin*[a]
Abstract: A transition-metal-free method for the dehydrogenative N–
N coupling of secondary amines has been accomplished. This
oxidative KI-KIO4 protocol is mild and operationally simple. A diverse
range of diphenylamines, carbazoles and N-alkylanilines readily
undergo N–N homo-coupling effectively. Notably, the N–N cross-
coupling of two different arylamines is also demonstrated, which
provides a straight-forward approach to the complex N–N structures.
(Table 1). Like other oxidants we tried, KIO4 failed to render any
reaction alone (entry 1). Delightfully, after the additive screening,
a dramatic and positive effect was observed. It afforded a
quantitative yield of the dimeric product 1 when catalytic amount
of KI or KI3 was added into the reaction (entries 2-6). We chose
KI as the additive for the following experiments with different
oxidants (entries 7-14). NaClO indeed worked for the oxidation
although with a moderate yield of 61% (entry 13). The expensive
PhIO and PhI(OAc)2 also performed well with high yields (entries
13 and 14). This oxidative N–N coupling reaction could be
carried out in a variety of solvents (See Supporting Information),
such as CH2Cl2 and MeOH among others (entries 15 and 16).
Introduction
The N–N bonds are widely found in natural products,[1]
pharmaceutical agents[2] and organocatalysts.[3] Compared to
the C–C and C–N bonds which have received numerous elegant
methods to enable their chemical synthesis, the N–N bond
formation is less explored. Although simple substrates
containing an N–N bond can be prepared from hydrazine, this is
a non-viable option for complex molecules due to the overall
inefficiency of multiple functionalization steps. Moreover, most
hydrazine building blocks are highly carcinogenic and need extra
safety precaution. Dehydrogenative coupling is drawing much
attention because of high efficiency, atom economy and minimal
environmental impact.[4] However, the traditional methods for
direct N–N bond formation featured stoichiometric transition-
metal oxidants, such as KMnO4 which was still used frequently
nowadays (Figure 1, path A).[5] Cu-catalyzed aerobic oxidation
approach represented a major advance in this field. Several
protocols were developed since Tsuji’s seminal work (Figure 1,
path B).[6] Very recently, an Fe-catalyzed version had also been
reported (Figure 1, path C).[7] Remarkably, electrochemistry has
experienced a renaissance in the field of organic synthesis,[8]
which leads to the successful application in N–N bond
construction (Figure 1, path D).[9] Herein we describe an
operationally simple, transition-metal-free method for the
dehydrogenative N–N coupling of secondary amines with
KI/KIO4 (Figure 1, path E).
While
a
nitrogen radical–radical coupling mechanism is
preferred, we could not exclude other pathways at this stage.
KMnO4, Na2Cr2O7, PbO2 or AgO
path A
Cu salt, O2
path B
R1
R2
R2
H
N
N
KI-KIO4
R1
R2
N
path E: this work
R1
arylamine
hydrazine
Fe salt, O2
path C
electrochemical oxidation
path D
Figure 1. Dehydrogenative N–N coupling reactions.
With the optimal conditions in hand, we sought to evaluate the
generality of the dehydrogenative N–N coupling protocol. Firstly,
good to high yields of tetraphenylhydrazines could be obtained
from diphenylamines bearing both electron-withdrawing and
electron-donating groups (Scheme 1). The reaction of
diphenylamines was typically clean with almost no C–N coupling
byproduct observed, thus the N–N coupling products could be
separated easily.
Application of this oxidative N–N coupling method to
carbazoles at 80 ºC furnished bicarbazoles effectively (Scheme
2). Similar to the previous reports,[6e,9a] carbazoles lacking
substitution at one or both of the 3- and 6-positions suffered
from C–N coupling side reactions to some extent. It is of note
that the halide substituents on aryl rings are useful for the further
transformation. Recently, several natural products with the
bicarbazole core structure were isolated.[10] Therefore, this N–N
coupling method provides a practical approach to the total
synthesis of these bioactive natural products.
Results and Discussion
We began our investigation into this dehydrogenative N–N
coupling by subjecting bis(4-bromophenyl)amine to different
transition-metal-free oxidants in MeCN at room temperature
[a]
Mr. D. Yin, Prof. Dr. J. Jin
CAS Key Laboratory of Synthetic Chemistry of Natural Substances
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032, China
E-mail: jjin@sioc.ac.cn
http://people.ucas.edu.cn/~jjin
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900763
European Journal of Organic Chemistry
COMMUNICATION
R1
R2
Table 1. Optimization of the Reaction Conditions.
H
N
KI (10 mol%)
Br
Br
H
N
KI (10 mol%)
KIO4 (1.5 equiv.)
N
N
KIO4 (1.5 equiv.)
N
N
R1
R2
MeCN (5 mL)
Br
Br
MeCN (5 mL)
rt, 8 h
80 °C, 8 h
0.5 mmol
carbazole
0.5 mmol
R1
R2
Br
Br
N−N product[a]
bis(4-bromophenyl)amine
N−N product 1
Cl
Cl
Br
Br
I
I
Entry
Yield (%)[a]
Additive
Oxidant
Conversion (%)
1
−
KIO4
0
100
0
0
99
0
N
N
N
N
N
N
2
KI
KBr
KCl
I2
KIO4
3
KIO4
4
KIO4
0
0
5
KIO4
0
0
Cl
Cl
Br
Br
Br
I
I
11, 87%
12, 83%
13, 84%
6
KI3
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
KIO4
100
0
99
0
7
KIO3
8
NaBrO3
NaClO4
NaClO3
NaClO2
NaClO
PhI(OAc)2
PhIO
0
0
Cl
9
N
N
0
N
N
N
N
0
10
11
12
13
14
15b
16c
0
0
Cl
0
0
100
100
100
100
64
61
96
96
99
64
Br
14, 33%
15, 51%
16, 69%
t-Bu
Me
Me
t-Bu
KIO4
KIO4
N
N
N
N
[a] Yields determined by H NMR using 1,3-benzodioxole as the internal
standard. [b] CH2Cl2 used as the solvent. [c] MeOH used as the solvent.
Me
Me
t-Bu
t-Bu
17, 98%b
18, 58%
R1
R2
H
N
KI (10 mol%)
Scheme 2. Oxidative Coupling of Carbazoles. [a] Isolated yields. See
Supporting Information for experimental details. [b] Reaction performed at
room temperature for 12 h.
KIO4 (1.5 equiv.)
N
R1
R2
N
MeCN (5 mL)
rt, 8 h
0.5 mmol
Oxidative dimerization of N-alkylanilines was also feasible
under the dehydrogenative conditions (Scheme 3). N-Methyl,
ethyl, isopropyl and cyclic anilines afforded the corresponding
N–N coupling products in moderate to high yields. In general,
the electron-richer substrates which are more prone to be
oxidized exhibit the higher reactivity.
R1
R2
N−N product[a]
diphenylamine
I
I
I
I
F
F
Cl
N
N
N
N
N
N
Finally, the N–N cross-coupling of two different arylamines
were explored (Scheme 4). When bis(4-bromophenyl)amine and
a carbazole substrate with a 1:1 ratio were subjected to the
oxidative conditions, a high-level cross-coupling occurred while
almost no homo-coupling product was observed. The cross-
coupled products of up to 85% yields showed significantly
greater-than-statistical selectivity (50% statistical yield for the 1:1
substrate ratio). Remarkably, a quantitative yield of the cross-
coupled product 36 was obtained from 1:1 ratio of bis(4-
bromophenyl)amine and bis(4-iodophenyl)amine. Moreover, the
1:1 mixture of bis(4-bromophenyl)amine and 4-bromo-N-
methylaniline afforded a 72% yield of the cross-coupled product
37. The final example showed that 3,6-di-tert-butyl-9H-carbazole
could also cross-couple with 4-bromo-N-methylaniline. The
origin of the cross-coupling outcome might be the quite weak N–
N bond of tetraphenylhydrazines (e.g., BDE = 23.5 kcal/mol for
Ph2N–NPh2).[6e,11] The dimerization of bis(4-bromophenyl)amine
should be reversible, which eventually shifts the equilibrium to
the more stable cross-coupled products. The above hypothesis
was supported well by the experiment shown in Scheme 5.
Cl
2, 95%
3, 88%
4, 85%
Br
Me
Me
N
N
N
N
N
N
Br
Me
Me
Me
Me
5, 91%
6, 65%
7, 96%
Me
t-Bu
t-Bu
N
N
N
N
N
N
t-Bu
t-Bu
Me
Me
8, 92%
9, 90%
10, 90%
Me
Scheme 1. Oxidative Coupling of Diphenylamines. [a] Isolated yields. See
Supporting Information for experimental details.
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10.1002/ejoc.201900763
European Journal of Organic Chemistry
COMMUNICATION
R1
R2
When an 1:2 mixture of the homo-coupling product 1 and 3,6-di-
tert-butyl-9H-carbazole was subjected to the reaction conditions
for 8 hours, it furnished the cross-coupling product 35 in 21%
yield along with a 69% yield of bis(4-bromophenyl)amine.
R1
R2
KI (10 mol%)
N
H
KIO4 (1.5 equiv.)
N
N
H
N
MeCN (5 mL)
R1
80 °C, 8 h
H
N
Br
Br
Br
Br
KI (10 mol%)
R2
N−N product[a]
R2
R2
0.25 mmol + 0.25 mmol
KIO4 (1.5 equiv.)
N
N
R1
Cl
Cl
Br
Br
I
I
MeCN (5 mL)
80 °C, 8 h
0.5 mmol
R1
N−N product[a]
N-alkylaniline
N
N
N
N
N
N
F
F
Cl
Br
Me
N
Me
Me
Me
Me
Br
Br Br
Br Br
Br
N
N
N
N
28, 76%
29, 62%
30, 72%
N
Br
Me
Cl
Br
Cl
19, 38%
20, 45%
21, 53%
N
N
N
N
N
N
Me
Br
Me
Me
Me
Me
Me
N
N
N
N
N
Br
Br Br
Br Br
Br
I
N
31, 85%
32, 75%
33, 81%
Me
Me
Me
t-Bu
t-Bu
Me
Br
I
22, 42%b
23, 79%b
24, 60%
N
N
N
N
N
N
Br
Br
Me
Me
N
N
Me
Me
N
N
N
N
Br
Br Br
Br Br
Br
34, 76%
35, 85%
36, 98%b
Br
Br
Br
25, 96%c
26, 58%
27, 45%
Br
Me
N
Me
Scheme 3. Oxidative Coupling of N-Alkylanilines. [a] Isolated yields. See
Supporting Information for experimental details. [b] Reaction performed at
room temperature for 8 h. [c] Reaction performed at 40 ºC for 4 h.
N
N
N
Br
Br
t-Bu
t-Bu
37, 72%
38, 45%
Scheme 4. Selective N–N Cross-Coupling. [a] Isolated yields. See Supporting
Information for experimental details. [b] Reaction performed at room
temperature for 8 h.
Br
Br
Br
t-Bu
t-Bu
N
N
N
N
Br
Br
Br
KI (10 mol%)
1
35
KIO4 (1.5 equiv.)
0 h: 0.125 mmol, 50 %
8 h: 0 mmol, 0%
0 h: 0 mmol, 0 mol%
8 h: 0.053 mmol, 21%
MeCN (5 mL)
t-Bu
t-Bu
80 ℃
Br
Br
N
H
N
H
diphenylamine
0 h: 0 mmol, 0 mol%
8 h: 0.173 mmol, 69%
carbozole
0 h: 0.25 mmol, 100 %
8 h: 0.178 mmol, 71%
Scheme 5. The possible origin of the cross-coupling.
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10.1002/ejoc.201900763
European Journal of Organic Chemistry
COMMUNICATION
Organic Chemistry, and CAS Key Laboratory of Synthetic
Chemistry of Natural Substances.
Conclusion
In summary, we have developed a transition-metal-free method
for the dehydrogenative N–N coupling of secondary amines with
KI/KIO4. The substrate scope includes but not limited to various
diphenylamines, carbazoles and N-alkylanilines, furnishing
homo-coupled tetraphenylhydrazines, bicarbazoles and dialkyl-
diphenylhydrazines effectively. Moreover, the N–N cross-
coupling of two different arylamines has also been demonstrated.
This reaction is mild and operationally simple, which we
anticipate would find broad applications in N–N bond formation.
Further studies on the mechanism and extension of the KI/KIO4
system are currently undergoing in our lab.
Keywords: metal-free • N–N coupling • diphenylamine •
carbazole • N-alkylaniline
[1]
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9074-9077.
[6]
Experimental Section
General Procedure for the N–N cross-coupling: To an 8 mL vial
equipped with a Teflon septum and a magnetic stir bar was charged KI
(8.3 mg, 0.05 mmol, 0.1 equiv.), KIO4 (172.5 mg, 0.75 mmol, 1.5 equiv.),
secondary amine (0.50 mmol, 1.0 equiv.), and 5 mL of MeCN. The
reaction mixture was degassed by sparging with nitrogen for 10 min with
an outlet needle, and then reacted at room temperature or 80 ºC. Upon
reaction completion as judged by TLC and LCMS (4-12 hours), the
reaction mixture was concentrated in vacuo. Purification of the crude
product by flash chromatography on silica gel or aluminium oxide neutral
using petroleum ether afforded the desired product.
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Acknowledgements
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Financial support was provided by the “Thousand Plan” Youth
program, Chinese Academy of Sciences, Shanghai Institute of
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10.1002/ejoc.201900763
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
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COMMUNICATION
Dehang Yin, Jian Jin*
N
H
N
H
KI/KIO4
KI/KIO4
N
N
N
N
Page No. – Page No.
H
N
H
N
Homo-Coupling
Cross-Coupling
Transition-Metal-Free
Dehydrogenative N–N Coupling of
Secondary Amines with KI/KIO4
Br
Br
Br
Br
Iodine brother do it together: With the recipe of KI/KIO4, a transition-metal-free
method for the dehydrogenative N–N coupling of secondary amines has been
accomplished. A diverse range of diphenylamines, carbazoles and N-alkylanilines
readily undergo N–N homo-coupling effectively. Notably, the N–N cross-coupling of
two different arylamines is also demonstrated, which provides a straight-forward
approach to the complex N–N structures.
Key Topic: N–N coupling
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