A family of low molecular-weight, organic catalysts for reductive C-C bond formation

Article abstract of DOI:10.1039/c5cc03580e

Hydrazines form a new family of low molecular-weight reducing agents for diazonium salts. Using only small amounts of hydrazine catalyst, the coupling of diazonium salts to a variety of reactive partners has been achieved, without the requirement for either metal adjuvants or irradiation with visible or ultraviolet light. The generality of the concept proposed herein as well as its advantages in the preparative scale is outlined and discussed.

Full text of DOI:10.1039/c5cc03580e

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COMMUNICATION
A family of low molecular-weight, organic catalyst for reductive C-
C bond formation
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
a
a
a
a
Saad Shaaban, Anaïs Jolit, Desislava Petkova, and Nuno Maulide
www.rsc.org/
Hydrazines form a new family of low molecular-weight reducing agents for diazonium salts. Using only small amounts of a
hydrazine catalyst, the coupling of diazonium salts to a variety of reactive partners has been achieved, without the
requirement for either metal adjuvants or irradiation with visible or ultraviolet light. The generality of the concept
proposed herein as well as its advantages in preparative scale are outlined and discussed.
Introduction
without the need for any metal adjuvant or irradiation with
Diazonium salts are well-known highly reactive species in
1
organic synthesis. Despite their commercially important
2
application in the dye industry, diazonium salts function as
light.
ideal sources of organic radicals that engage in several
3
important transformations such as the Meerwein arylation or
Results and discussion
1
5
4
5
the Sandmeyer and Pschorr reaction families. Since the
We were inspired by the work of Shevlin et al. who aimed to
isolate stable tetrazenes by reacting phenyldiazonium
tetrafluoroborate with phenylhydrazine (Scheme 1). However,
those authors were not able to isolate the tetrazene
intermediate but instead observed a complex mixture that
featured benzene as major component in 54% yield and
several other minor compounds. The formation of most of the
components of the mixture was attributed to the intermediacy
of free radicals, as supported by spectroscopic studies
6
7
and renaissance of photoredox catalysis, many
advent
photocatalysts have been shown to catalyse the single
electron transfer reduction of diazonium salts to organic
radicals. In particular, ruthenium(II) and iridium(III) complexes
have been successfully applied in many reactions that exploit
their remarkable reactivity in either reductive or oxidative
8
quenching pathways upon visible light (440nm) excitation.
The relatively high price of those noble/precious metal
complexes has subsequently led to the development of
alternatives. Namely, several organic dyes proved to be
(CIDNP).
9
efficient photocatalysts upon excitation with visible light. For
9a,11
and perylene diimides
1
instance, Eosin Y, acridinium salts
0
1
2
PDI) were all successfully used in photocatalytic organic
(
transformations. A recurrent structural feature of these
organic dye catalysts is the presence of extended π-surfaces
(
mandated by the need to effectively absorb visible light) and Scheme 1 Reaction of phenyldiazonium salt with phenylhydrazine as
reported by Shevlin et al..
1
high molecular-weight frameworks. Recentely, Carrillo et al.
3
15
described the use of ascorbic acid as an initiator for a C-H
1
4
Arylated heteroarenes have proved to be of interest for
various applications, such as material sciences and
arylation of anilines. Herein we describe a family of low-
molecular weight organic catalyst that promote a range of C-C
bond forming reactions of diazonium salts, and achieve so
1
6
biomedicine. One efficient route to install the aryl-heteroaryl
bond is the Meerwein arylation, a cross-coupling reaction
between heteroarenes and diazonium salts that is assumed to
a.
17
University of Vienna, Institute of Organic Chemistry, Währinger Strasse 38, 1090
Vienna, Austria.
nuno.maulide@univie.ac.at; http://maulide.univie.ac.at
† Electronic Supplementary Informaꢀon (ESI) available: characterisation data for
new compounds and ancillary experiments. See DOI: 10.1039/x0xx00000x
proceed by a free radical mechanism.
We hypothesized that a hydrazine such as phenylhydrazine
(employed in the work of Shevlin) could function as a novel
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reducing agent towards aryl diazonium salts. However, it was conditions. Notably, the carbon-halogen bonds in 4g and 4i
crucial to generate the radical intermediate under conditions were not affected and could serve as reactive handles for
1
which would (a) avoid the occurrence of either homocoupling further elaboration. A further potential advantage of this
9
or hydrogen abstraction (as seen by Shevlin), (b) enable its system is highlighted in Scheme 3. N,N-dimethylhydrazine 3c
,
efficient trapping by the heteroarene partner, (c) prevent which has a very low molecular weight (MW = 60 g/mol, more
unwanted disproportionation reactions (such as, e.g. leading than 11 times lower than eosin Y), was used to scale up the
to an azide and an aniline, as originally also observed by coupling reaction between nitrobenzene diazonium salt 1a and
Shevlin) and, most importantly, (d) allow rebound electron- furan 2b to yield 4b in ca. 85% yield in 15 min. Remarkably,
transfer from the coupling adduct to generate the final, only 7.6 mg of catalyst was used for 12.6 mol of substrate (3g
neutral biaryl product.
scale, 1 mol% catalyst). For the sake of comparison, to achieve
the same reaction König’s elegant photochemical method
1
0b
would require 87 mg of eosin Y (1 mol%) .
From the outset of our studies on the Meerwein arylation of
thiophene, it soon became apparent that hydrazines might
have the potential to function as catalyst in such a coupling,
thus addressing all the above concerns in a fell swoop (detailed
optimisation is included as Table S1 of the ESI). Strikingly,
yields of coupling reactions were unchanged when the
reaction was performed in the dark, showing that light plays
no appreciable role in this transformation. We chose
Scheme 3. Scale up of the α-arylation of furan with p-nitrobenzene
diazonium salt using N,N-dimethylhydrazine 3c as catalyst.
4-aminomorpholine 3d to pursue our studies due to both
practical considerations and its low price. Importantly, the
catalyst proved to be essential for the formation of 4a, as only
traces of the desired product were obtained under similar
At this juncture, we inquired whether this mode of redox
catalysis could be extended to other related transformations.
The synthesis of α-aryl ketones is a challenging significant
1
8
2
0
conditions if it was absent from the reaction mixture.
reaction. It was recently shown that the capture of
2
diazonium salts with enolacetates led to this motif.
1
Nevertheless, the reported methodologies mandate the use of
21b
H2N
N
O
21a
transition metal catalysts, transition metal photocatalysts
N2BF4
3d (5 mol%)
DMSO (0.18M), r.t.
X
21c
+
or stoichiometric amounts of base. We thus were intrigued
by the possibility of employing hydrazine catalysis for this
process (Scheme 4).
X
R
1
2
R
4a-l
(
20 equiv.)
S
O
N
O
Boc
O2N
2
O N
2
O N
NC
4a (15 min, 63%) 4b (15 min, 95%)
4c (15 min, 81%)
4d (3 h, 81%)
O
O
S
O
MeO2C
NC
Br
CF3
4e (3 h, 66%)
4f (10 h, 66%)
4g (30 min, 75%)
4h (15 min, 55%)
O
N
N
O
Boc
Boc
MeO
NC
MeO2C
Cl
4
i (15 min, 63%) 4j (3 h, 89%)
4k (10 h, 69%)
4l (3 h, 55%)
Scheme 2. Scope of the α-arylation of heteroarenes with various
diazonium salts using the optimised conditions detailed in the
supporting information. The yields are given for the isolated products.
Scheme 4. Preparation of α-aryl ketones via reduction of diazonium
salts with hydrazine 3d. Yields refer to isolated products.
The scope of this hydrazine-catalyzed C-H arylation of
heteroarenes with various aryl diazonium salts was then
Several aryl diazonium salts 1 were therefore treated with
alkenyl acetates in presence of 10 mol% of hydrazine 3d in
5
examined using the best conditions found. As shown in dimethylformamide (DMF) to prepare α-arylketone products
6.
Scheme 2, a range of functional groups, such as nitro, cyano, A series of α-aryl methylketones and α-aryl arylketones could
be synthesized in moderate to good yield. The reaction was
ester, and trifluoromethane are compatible with the reaction
2
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tolerant of several functional groups, such as nitro, ester and that the hydrazine catalyst is present in the reaction mixture
cyano substituents.
We further applied this catalytic system to the preparation of
(by both LC-MS and NMR analysis) after full conversion has
been reached, thus establishing catalytic behaviour. Based on
3
b,10b,15
2
-substituted thiophenes
methylthio) diazonium
transformation has been previously reported using transition
8
from the corresponding ortho-
the above observations and previous literature,
a
(
tetrafluoroborate 1h This
.
general mechanism for the couplings of diazonium salts
catalysed by 4-aminomorpholine (typified by the Meerwein
arylation) is proposed in Scheme 8.
2
2a
metal catalysis
or visible light photoredox catalysis with
2
2b
eosin Y. 4-Aminomorpholine 3d was able to catalyse this
transformation furnishing the corresponding benzothiophenes
in good to moderate yields (Scheme 5).
Scheme
5. Preparation of 2-substituted benzothiophenes via
hydrazine-catalysed coupling of diazonium salt 1h and alkynes 7. Yields
refer to isolated products.
Furthermore, the arylation of quinones with diazonium salts is
an interesting transformation due to the important role of
functionalized quinones in medicinal chemistry and biologically
active compounds. Bearing this in mind, this reaction was also
achieved employing 4-aminomorpholine 3d as catalyst and the
Scheme 8
. Proposed catalytic cycle for the hydrazine-catalysed
coupling of diazonium salt 13 and heteroarene 17
.
1
,
5
2
3
We believe that formatiom of tetrazene 14
via reaction of
results are summarized in Scheme 6.
diazonium salt 13 with the hydrazine catalyst 3d, will generate
aryl radical 16 and diazenium radical cation 15 and is driven by
the release of nitrogen gas. Radical 16 is subsequently
intercepted by a reactive unsaturation typified by 17, to form
2
4
radical adduct 18. Oxidation of 18 via SET of 15 to the
corresponding carbocation 19 regenerates the hydrazine
catalyst 3d and aryl radical 16, enabling turnover.
Conclusions
Scheme 6. Hydrazine-catalysed C-H arylation of quinones with
diazonium salts. Yields refer to isolated products.
In summary, we have shown that simple hydrazines form a
new family of low molecular weight reducing agents that allow
the catalytic coupling of diazonium salts to electron-rich
heteroarenes, enol acetates, alkynes or benzoquinones under
simple conditions. Notably, these catalysts’ low molecular
weight ensures unrivalled practicality when one considers the
upscaling of this type of chemistry. That hydrazines can
function as catalytic activators for diazonium salts, shown by
Scheme 7. Trapping the aryl radical intermediate with TEMPO.
Finally, we attempted to trap the putative aryl radical their presence after full conversion has been achieved, is a
intermediate, presumably formed upon diazonium salt new type of reactivity bound to inspire the development of
reduction, with TEMPO 11
phenyldiazonium salt 1g was exposed to a catalytic amount of
-aminomorpholine 3d in the presence of 2 equiv. of TEMPO.
.
As shown in Scheme 7, further transformations.
4
Acknowledgements
The expected covalent adduct, 2,2,6,6-tetramethyl-1-
phenoxypiperidine 12, was isolated in 44% yield. Additional
experiments (see Supporting Information for details) reveal
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-
g.mol ,
1
Generous financial support of this research by the Deutsche
Forschungsgemeinschaft (Grants MA 4861/1-2 and MA
13 Eosin
Y
Mw:
691.85
acridinium
-
tetrafluoroborate Mw: 388.9 g.mol , PDI Mw: 710,31
1
-
1
4861/4-2) and the University of Vienna is acknowledged.
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,
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