Ancillary ligand-free copper catalysed hydrohydrazination of terminal alkynes with NH2NH2

Article abstract of DOI:10.1039/c5cc10427k

An efficient and selective Cu-catalysed hydrohydrazination of terminal alkynes with parent hydrazine is reported. The methodology tolerates a broad range of functional groups, allows for the synthesis of symmetrical and unsymmetrical azines, and can be extended to hydrazine derivatives and amines.

Full text of DOI:10.1039/c5cc10427k

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DOI: 10.1039/C5CC10427K
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Ancillary Ligand-Free Copper Catalysed Hydrohydrazination of
Terminal Alkynes with NH2NH2
J. L. Peltier, R. Jazzar, M. Melaimi and G. Bertrand*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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An efficient and selective Cu-catalysed hydrohydrazination of
Based on the positive results observed with gold
terminal alkynes with parent hydrazine is reported. The catalysts,13 we questioned if copper complexes could also
methodology tolerates a broad range of functional groups, allows promote the hydrohydrazination of alkynes. It is interesting to
for the synthesis of symmetrical and unsymmetrical azines, and note that so far, even for the hydroamination reaction, there
can be extended to hydrazine derivatives and amines.
are only a few reports dealing with the Cu-catalysed
intermolecular version,14 although there are examples of
intramolecular reactions.15
Driven by environmental and industrial concerns, the
development of sustainable methodologies providing clean
and selective synthetic transformations has risen over the
years to become a major societal challenge.1 In this context,
the development of atom-efficient routes to carbon-nitrogen
containing products using readily accessible bulk materials
such as parent hydrazine is of special interest. However,
NH2NH2 is a strong reducing agent, which can induce the
formation of inactive metal(0),2 or lead to the formation of
inert Werner complexes.3 Consequently, very few examples of
catalytic reactions involving this reagent have been reported.
Lundgren and Stradiotto,4 and Buchwald et al.5 have
demonstrated that Pd- and Cu-catalysed cross-coupling of
hydrazine with aryl chlorides and tosylates was possible
providing the use of an electron rich bulky P-ligand. We6 and
others7 have also shown that the hydrohydrazination of
unactivated alkynes and allenes is efficiently promoted by
cationic (L)Au(I) complexes (L: CAAC,8 PyrNHC,9 MIC,10 BAC,11
saNHC12) (Fig. 1).
Optimization of the reaction was performed using a
stoichiometric
mixture
of
parent
hydrazine
and
o
phenylacetylene, as a model substrate, at 100 C for 12h with
5 mol% of copper complex (Table 1). In the presence of 5mol%
KB(C6F5)4 (KBArF), both (IPr)CuCl16 and (CAAC)CuCl17 showed
moderate activity (Entries 1 and 2), while the bulkier
(IPr*)CuCl18 afforded complete conversion, allowing the
isolation of 1a in 83% yield (Entry 3). (CAAC)CuOTf17 showed
minimal activity likely due to the coordinating nature of the
OTf counter-anion (Entry 4). At this stage, control experiments
were performed to confirm these initial observations. To our
surprise, while no reaction was observed using either KBarF,
(IPr*)CuCl or CuCl alone (Entries 5-7), quantitative formation of
hydrazine 1a occurred in the presence of a stoichiometric
mixture of CuCl/KBArF (5 mol%) (Entry 8). Replacing CuCl by
CuCl2 also led to full conversion albeit in lower yield (86% -
Entry 9). Noteworthy, the reaction appears to be limited to
non-polar solvents such as benzene or toluene (Entries 10-12).
Potassium or silver salts with weakly coordinating anions are
broadly used for the in situ preparation of cationic metal
species. However, as previously observed by Hashmi et al. with
the (saNHC)AuCl system,7 replacing KBArF by KBPh4, KSbF6, or
AgOTf, inhibits the reaction (Entries 13-15). Since Bergman19
has shown that the hydroamination of alkenes with anilines
could be promoted by H(Et2O)2.5B(C6F5)4, we tested the
hydrohydrazination in the presence of 5 mol% of HBArF, but
no conversion occurred. (Entries 16-17). Finally, a mercury test
was performed to evaluate alternative heterogeneous catalytic
pathways involving the formation of colloidal copper
nanoparticles (Entry 18). Under these conditions, catalysis still
proceeded which is consistent with a homogeneous catalytic
system.
Figure 1: Carbene ligand previously used in gold-catalysed hydrohydrazination
N
N
N
(iPr)2N
N(iPr)2
N
N
N
N
N
pyrNHC
saNHC
CAAC
MIC
BAC
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Table 1: Optimization of the reaction conditions
Table 2: Scope of the hydrohydrazination of terminal alkynes with NH NH
DOI: 10.1039/C5CC10427K
2
2
NH2
N
NH2
CuCl (5 mol%)
(cat.) (5 mol%)
N
+
+
H2N NH2
R
H2N-NH2
Ph
Additive (5 mol%.)
Solvent, 100 oC, 12 h
Ph
KBArF (5 mol%.)
C6D6, 100 oC, 12 h
R
1a
1a-1k
Solvent
1a (%)a
Entry
Catalyst
Additive
NH2
NH2
N
NH2
N
N
(IPr)CuCl
(CAAC)CuCl
(IPr*)CuCl
(CAAC)CuOTf
-
KBArF
KBArF
KBArF
-
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
THF
66
64
83b
22
0
1
2
3
95%
1a
86%
nBu
1b
87%
1c
MeO
4
5
KBArF
-
NH2
NH2
N
NH2
6
CuCl
0
NH2
N
N
7
(IPr*)CuCl
CuCl
-
0
8
KBArF
KBArF
KBArF
KBArF
KBArF
KBPh4
KSbF6
AgOTf
HBArF
HBArF
KBArF/Hg(0)
99
86
0
83%a
73%
1e
89%
1f
9
CuCl2
CuCl
Br
1d
10
11
12
13
14
15
16
17
18
NH2
NH2
N
NH2
CuCl
CHCl3
0
N
N
CuCl
Toluene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
99
< 1
< 1
< 1
0
CuCl
71%a
76%a
22%a
CuCl
N
1g
1h
1i
CuCl
CuCl
a 16h reaction time
Table 3: Hydrohydrazination and hydroamination of phenyl acetylene.
-
0
CuCl
99
R
N
CuCl (5 mol%)
Et
Ph
Ph
+
Ph
R-NH2
N
N
N
N
N
Dipp
Dipp
Dipp Dipp*
Dipp*
Ph
Et
KBArF (5 mol%.)
C6D6, 100 oC, 12 h
CuCl
(CAAC)CuCl
CuCl
CuCl
(IPr*)CuCl
Ph
1j-1m
Ph Dipp*
(IPr)CuCl
Ph
N
N
aDetermined by 1H NMR spectroscopy using hexamethylbenzene as internal
standard; bisolated
N
N
N
N
H
80%
1k
92%
1j
We then evaluated the scope of the reaction using CuCl (5
mol%), KBArF (5 mol%), and benzene as solvent. Under these
conditions, a broad range of terminal aryl alkynes was reacted
with parent hydrazine to yield the hydrazones 1a-1i in good to
excellent yields (Table 2). The reaction also appears to work
with benzyl alkyne but is slower with alkyl substituted alkynes
as observed with 1-hexyne, since compound 1i was obtained in
only 22% yield after 16h. However, this protocol is quite
straightforward as demonstrated by a gram-scale synthesis
using phenylacetylene and parent hydrazine. Under the
optimized conditions, 1.17 g (89% yield) of hydrazone 1a was
obtained.
To demonstrate the broad scope of this ancillary ligand-
free copper catalysed process, phenyl acetylene was reacted
with 1,1-dimethylhydrazine and phenylhydrazine, as well as
with primary amines such as n-propylamine and aniline, and
the corresponding products were obtained in greater than 78%
yield (Table 3).
Ph
86%
1l
78%
1m
During our study we observed the formation of trace
amounts of azines 2. These products, which result from a bis-
hydrohydrazination reaction, are formed whenever parent
hydrazine was used sub-stoichiometrically. Azines have been
used as synthetic intermediates,20 and recently received much
attention due to their interesting physical21 and biological
properties.22 Under the standard conditions, using half
equivalent of parent hydrazine we were able to obtain the
corresponding azines 2a-2d in good to excellent yields (Table
4). Furthermore, by sequential addition of two different
alkynes, we were able to cleanly prepare unsymmetrical azines
2e-2f (Table 5).
2 | J. Name., 2012, 00, 1-3
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Table 4: Bis(hydrohydrazination) of terminal alkynes
3
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L. Klinkenberg and J. F. Hartwig, Angew. Chem. Int. Ed., 2011,
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CuCl (5 mol%)
50, 86.
NH2-NH2
4
5
6
R. J. Lundgren and M. Stradiotto, Angew. Chem. Int. Ed.,
2010, 49, 8686.
N
Ar
Ar
Ar
N
KBArF (5 mol%.)
C6D6, 100 oC, 12 h
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Int. Ed., 2013, 52, 3434.
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Angew. Chem. Int. Ed., 2012, 51, 6172.
2a-2d
OMe
N
N
N
N
92%
2a
89%
MeO
2b
7
8
9
H2N
Br
N
N
N
N
NH2
Br
10 G. Guisado-Barrios, J. Bouffard, B. Donnadieu and G.
Bertrand, Angew. Chem. Int. Ed., 2010, 49, 4759.
11 V. Lavallo, Y. Canac, B. Donnadieu, W. W. Schoeller and G.
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85%
90%
2c
2d
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Oeser, Chem. Eur. J., 2012, 18, 3827; (b) R. Manzano, F.
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2199.
13 A. S. K. Hashmi and G. J. Hutchings, Angew. Chem. Int. Ed.
Engl. 2000, 39, 2285.
Table 5: Stepwise synthesis of unsymmetrical azines
CuCl (5 mol%)
NH2-NH2
NH2
N
Ar
F
+
Ar
Ph
N
Ph
N
N
KBArF (5 mol%.)
C6D6, 100 oC, 12 h
14 (a) L. Zhou, D. S. Bohle, H. F. Jiang and C. J. Li, Synlett 2009,
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2e-2h
OMe
N
81%
2e
76%
2f
Ph
Ph
N
N
Ph
Ph
N
nBu
N
N
N
85%
2g
72%
2h
OMe
In summary, we have reported the first examples of
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17 L. Jin, D. R. Tolentino, M. Melaimi and G. Bertrand, Sci. Adv.,
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copper-catalysed hydrohydrazination of terminal alkynes with
NH2NH2. The methodology tolerates a broad range of
functional groups, allows for the synthesis of symmetrical and
unsymmetrical azines, and can be extended to hydrazine
derivatives and amines. In contrast to other metal catalysed
reactions allowing the functionalization of parent hydrazine,4-7
the process reported here is ancillary ligand-free and therefore
economically viable.
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S. J. Cazin and S. P. Nolan, Organometallics, 2011, 30, 5463.
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Acknowledgements
Thanks are due to the DOE (DE-FG02-13ER16370) for financial
support of this work.
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Notes and references
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2
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