A dehydrogenative homocoupling reaction for the direct synthesis of hydrazines from N-alkylanilines in air

Article abstract of DOI:10.1055/s-0030-1259520

A copper-catalyzed N-N bond-forming reaction was performed by a dehydrogenative homocoupling of N-alkylanilines, affording N,N-dialkyl-N,N- diphenylhydrazines in 72-88% yields. This new strategy has the advantages of direct synthesis from N-alkylanilines,

Full text of DOI:10.1055/s-0030-1259520

LETTER
569
A Dehydrogenative Homocoupling Reaction for the Direct Synthesis of
Hydrazines from N-Alkylanilines in Air
D
irec
t
Synthesis
o
u
f
H
ydrazines
e
from
N
-Alk
-
ylanilin
M
es ing Yan,a,c Zhi-Ming Chen,a Fei Yang,a Zhi-Zhen Huang*a,b
a
College of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. of China
Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
Fax +86(025)83686231; E-mail: huangzz@nju.edu.cn
b
c
College of Chemistry and Chemical Engineering, University of South China, Hengyang, Hunan 421001, P. R. of China
Received 1 December 2010
Initially, we examined the oxidative homocoupling of N-
methylaniline (1a), using CuBr (20 mol%) as a metal cat-
alyst and 4 Å molecular sieves (MS) as an additive at 95
°C in DMF under air for 24 hours. A trace amount of the
Abstract: A copper-catalyzed N–N bond-forming reaction was
performed by a dehydrogenative homocoupling of N-alkylanilines,
affording N,N¢-dialkyl-N,N¢-diphenylhydrazines in 72–88% yields.
This new strategy has the advantages of direct synthesis from N-
alkylanilines, using air as the oxidant, convenient manipulations, desired product 2a was obtained [Table 1, entry 1; for oth-
mild reaction conditions and moderate to good yields. A possible
er copper catalysts see Supporting Information (SI)].
mechanism by coordination and reductive elimination has been pro-
posed.
Gratifyingly, when N,N,N¢¢N¢-tetramethylethylenedi-
amine (TMEDA) was employed as a ligand, the yield was
Key words: homocoupling, oxidative dehydrogenation, copper
catalyst, direct synthesis, hydrazine
increased to 49% (Table 1, entry 2). After the survey of
other ligands, such as N¢,N¢-dimethylpropane-1,3-diamine
(DMAPA), and ethane-1,2-diamine (EDA), TMEDA
proved to be the best (Table 1, entries 3 and 4; also see SI).
Recently, oxidative dehydrogenative couplings are be-
coming an important strategy for modern organic synthe-
sis due to high efficiency, atom economy and minimal
environment impact.1 By dehydrogenative homocou-
pling, various symmetric C–C bonds can be formed di-
rectly.2 Many studies on the dehydrogenative
homocoupling of thiols to form S–S bond have been car-
ried out for the synthesis of disulfides.3 A few literatures
disclosed the formation of Si–Si4a and Sn–Sn4b bonds by
the direct homocoupling of hydrostannanes and second-
ary silanes, respectively. Different from the investigations
on the formations of S–S bonds and Sn–Sn bonds, the di-
rect formation of N–N bond by dehydrogenative coupling
was rarely reported.5 As a main class of compounds con-
taining N–N bonds, hydrazine derivatives are important
building blocks in organic synthesis,6 and usually show
significant biological activities.7 Most synthesis of them
are based on the compounds containing N–N or N=N
bonds.6,8 Besides, N-protected oxaziridines, ureas, and ni-
troarene can also be used as starting materials for the syn-
thesis of hydrazines.9–11 Tsuji revealed a protocol for the
direct synthesis of hydrazines from amines by copper-cat-
alyzed oxidative coupling.5a However, it seems that for N-
alkylanilines as starting materials, only one example, N-
methylaniline is suitable for this protocol to give N,N¢-
dimethyl-N,N¢-diphenylhydrazine in 52% yield. Herein,
we wish to report our recent work on the direct dehydro-
genative homocoupling of N-alkylanilines to afford tetra-
substituted hydrazines in satisfactory yields.
When metal oxides, such as CuO, SnO2, SeO2, and Fe2O3
were employed as co-catalysts, the yield of 2a increased
remarkably, among which CuO was the most effective
(Table 1, entries 5–8; also see SI).12 In the presence of
CuO, other copper catalysts, such as CuCl, CuI,
CuCl2·2H2O, and CuSO4·5H2O also gave the desired
product in moderate to good yields (Table 1, entries 9–
12), but CuBr2 and Cu(OAc)2·H2O led to poor yields. It is
noteworthy that the oxidative homocoupling did not occur
in the absence of copper catalyst (Table 1, entry 15). Us-
ing oxygen instead of air resulted in a similar yield. When
the reaction was conducted under nitrogen, only trace hy-
drazine 2a was obtained, indicating that oxygen is crucial
for this reaction. Other oxidants, such as t-BuOOH, t-
BuOOt-Bu, and 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) led to poor yields (Table 1, entries 18–20). Polar
solvents, such as DMF, DMSO, and MeCN were suitable,
and DMF is an optimal solvent for the reaction (see SI).
Addition of 4 Å MS was favorable to the reaction.12,13 The
optimal reaction temperature was found to be 95 °C.
After screening of various copper catalysts, ligands, metal
oxides, oxidants, bases, reaction temperatures and sol-
vents, we concluded that the optimized reaction should be
performed by the catalysis of CuBr (20 mol%) at 95 °C in
DMF using CuO (20 mol%) as a co-catalyst, TMEDA
(2.0 equiv) as a ligand and air as an oxidant. Under the op-
timized conditions, the scope of the reaction substrates
was investigated (Scheme 1).14 The experiments demon-
strated that various N-alkylanilines 1a–d performed the
homocoupling reaction smoothly to give the desired N,N¢-
dialkyl-N,N¢-diphenylhydrazines 2a–d in good yields.
The N-alkylanilines, 1e–j, bearing electron-donating
SYNLETT 2011, No. 4, pp 0569–0572
x
x.
x
x.
2
0
1
1
Advanced online publication: 27.01.2011
DOI: 10.1055/s-0030-1259520; Art ID: W18910ST
© Georg Thieme Verlag Stuttgart · New York

570
X. M. Yan et al.
LETTER
CuBr (20 mol%)
CuO (20 mol%)
TMEDA (2.0 equiv)
Table 1 Optimization of the Dehydrogenative Homocoupling Con-
R1
R1
N
ditionsa
R2
NH
N
R1
Me
NH
R2
R2
Me
N
K2CO3, 4 Å MS
DMF, air, 70–95 °C
CuBr (20 mol%)
additive (20 mol%)
ligand (2.0 equiv)
N
1a–l
2a–l
Me
K2CO3, 4 Å MS, DMF
air, Me 95 °C, 24 h
1a
Entry
1
2a
Me
Cu catalyst
CuBr
Additive Ligand
Yield (%)b
N
N
N
N
N
N
Me
–
–
trace
49
25
0
2a (84%)
2b (85%)
2c (82%)
2
CuBr
–
TMEDA
DMAPA
EDA
3
CuBr
–
Me
4
CuBr
–
N
N
N
N
N
N
5
CuBr
CuO
SnO2
SeO2
Fe2O3
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
CuO
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
84
82
78
75
70
78
81
80
58
32
0
Me
6
CuBr
2d (80%)
2e (86%)
2f (88%)
7
CuBr
Me
N
8
CuBr
N
N
N
9
CuCl
N
N
Me
10
11
12
13
14
15
16c
17d
18e
19f
20g
CuI
2g (78%)
2h (77%)
2i (82%)
CuCl2·2H2O
CuSO4·5H2O
CuBr2
Cu(OAc)2·H2O
–
OMe
Br
Cl
Me
Me
N
Me
N
N
N
N
N
Me
Me
2l (75%)
Me
Br
Cl
OMe
2j (82%)
2k (72%)
CuBr
82
trace
30
35
trace
Scheme 1 Dehydrogenative homocoupling for the direct synthesis
of hydrazines. The mixture of N-alkylaniline 1 (1.0 mmol), CuBr (20
mol%), CuO (20 mol%), TMEDA (2.0 equiv), K2CO3 (2.0 equiv) and
4 Å MS (0.1 g) in DMF (2.0 mL) was stirred at 70 °C or 95 °C for 8–
24 h under air. Compounds 1a–d or 1k–l were reacted at 95 °C for 12–
24 h and 1e–j were reacted at 70 °C for 8–12 h. Isolated yields are re-
ported.
CuBr
CuBr
CuBr
CuBr
a The mixture of 1a (1.0 mmol), Cu catalyst (20 mol%), metal oxide
(20 mol%), ligand (2.0 equiv), K2CO3 (2.0 equiv), 4 Å MS (0.1 g) in
DMF (2 mL) was stirred at 95 °C under air for 24–48 h.
b Isolated yields.
action temperature was lowered to room temperature, it
was found that o-semidines 4a–e were isolated in good
yields (Scheme 2).
c O2 (1 atm) was used as an oxidant.
d The reaction was carried out under N2 (1 atm) for 48 h.
e t-BuOOH was used as oxidant.
R1
CuBr (20 mol%)
R1
CuO (20 mol%)
R2
NH
f t-BuOOt-Bu was used as oxidant.
TMEDA (2.0 equiv)
NH
g DDQ was used as oxidant.
K2CO3, 4 Å MS
DMF, air, r.t., 12 h
R2
N
R2
R1
groups on benzene ring resulted in better yields, shorter
reaction time and lower reaction temperature as compared
to those bearing electron-withdrawing groups on benzene
ring (1k–l), and 4-nitro-N-alkylaniline did not undergo the
homocoupling reaction. 2-Methyl- or 2-methoxy-N-meth-
ylanilines and N-isopropylaniline were proved unreactive
probably due to steric hindrance. Interestingly, when 4-
methoxy- or 4-ethoxy alkylanilines 3a–e were employed,
no desired homocoupling product of hydrazine was ob-
served under the above optimal conditions. When the re-
3a R1 = Me, R2 = OMe
3b R1 = Et, R2 = OMe
4a 86%
4b 87%
4c 81%
4d 83%
4e 80%
3c R1 = n-Pr, R2 = OMe
3d R1 = Me, R2 = OEt
3e R1 = Et, R2 = OEt
Scheme 2 Dehydrogenative homocoupling for the direct synthesis
of o-semidines. General conditions: alkylaniline (1.0 mmol), CuBr
(20 mol%), K2CO3 (2.0 equiv), DMF (2.0 mL), TMEDA (2.0 equiv),
CuO (20 mol%) and 4 Å MS (0.1 g) under air at r.t. for 12 h. Isolated
yields are reported.
Synlett 2011, No. 4, 569–572 © Thieme Stuttgart · New York

LETTER
Synthesis of Hydrazines from N-Alkylanilines
571
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A possible mechanism for the direct synthesis of hydra-
zine 2 from N-alkylaniline 1 is depicted in Scheme 3. Ini-
tially, Cu(I) complex A is oxidized to peroxo-dicopper(II)
complex B by air.15 Then, the dicopper(II) complex B is
subjected to nucleophilic attack by N-alkylaniline 1 to
generate diamino complex C, followed by reductive elim-
ination to give the hydrazine 2. A successive oxidation of
copper(0) complex D to copper(I) complex A completes a
catalytic cycle. The presence of CuO in the reaction sys-
tem may promote the decomposition of dicopper(II) com-
plex B, facilitating the attack of N-alkylaniline 1.12
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L CIu
O2
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2
X
n
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A
O2
in air
O
II
II
0
B
LnCu
CuLn
LnCu
D
O
+ base
4 ArRNH
NRAr
NRAr
II
1
L Cu
n
2
ArRNNRAr
H2O
C
2
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Scheme 3 Proposed mechanism for the copper-catalyzed oxidative
dehydrogenative homocoupling of N-alkylanilines
In summary, we have developed a copper-catalyzed N–N
bond-forming reaction by the direct dehydrogenative ho-
mocoupling of N-alkylanilines, furnishing N,N¢-dialkyl-
N,N¢-diphenylhydrazines 2a–l in 72–88% yields. This
new strategy has the advantages of using air as oxidant,
direct synthesis from N-alkylanilines, convenient manip-
ulations, mild reaction conditions and good yields. A pos-
sible mechanism by coordination and reductive
elimination has also been proposed. Further studies on the
mechanism and extension of the copper-catalyzed oxida-
tive dehydrogenative homocoupling are currently under-
way.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial supports from the National Natural Science Foundation of
China (No. 20872059 and 21072091) and MOST of China (973 pro-
gram 2011CB808600) are gratefully acknowledged.
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Synlett 2011, No. 4, 569–572 © Thieme Stuttgart · New York

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X. M. Yan et al.
LETTER
equiv) and 4 Å MS (0.1 g) successively, and the reaction
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(14) General Experimental Procedure: To a solution of
N-alkylaniline 1 (0.107 g, 1.0 mmol) in DMF (2 mL) were
added CuBr (0.029 g, 0.2 mmol), TMEDA (0.232 g, 2.0
mmol), CuO (0.016 g, 0.2 mmol), K2CO3 (0.276 g, 2.0
mixture was stirred at 70 °C or 95 °C for 12–24 h in air. After
the reaction was completed, the mixture was filtered, and the
residue was washed with EtOAc (3 × 5 mL). Then, the
combined filtrates were concentrated in vacuum, and the
residue was purified by column chromatography (silica gel,
PE–EtOAc as eluent) to afford the desired hydrazine 2.
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Synlett 2011, No. 4, 569–572 © Thieme Stuttgart · New York

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