Transition-metal-free oxyarylation of alkenes with aryl diazonium salts and TEMPONa

Article abstract of DOI:10.1021/ja307638u

The reaction of readily available TEMPONa with aryl diazonium salts allows for clean generation of the corresponding aryl radicals along with TEMPO. Aryl radical addition to alkenes with subsequent TEMPO trapping provides the corresponding oxyarylation pr

Full text of DOI:10.1021/ja307638u

Communication
pubs.acs.org/JACS
Transition-Metal-Free Oxyarylation of Alkenes with Aryl Diazonium
Salts and TEMPONa
Marcel Hartmann, Yi Li, and Armido Studer*
Institute of Organic Chemistry, University of Munster, Corrensstrasse 40, 48149 Munster, Germany
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* Supporting Information
Whereas intramolecular variants of such processes are rather
well investigated,2,3 reports of intermolecular versions are rare.4
Recently, oxyarylation of alkenes with arylboronic acids or
arylsilanes using cationic Au complexes has been reported
independently by Toste5 and Lloyd-Jones.6 The addition of a
stoichiometric oxidant and elevated temperature are required
for these elegant gold-catalyzed oxyarylations. Radical reactions
can be conducted under mild conditions and tolerate many
functional groups, rendering such processes highly useful in
organic synthesis.7 More than a century ago, it was shown that
aryl diazonium salts are valuable precursors of aryl radicals
(Sandmeyer reaction).8 The Meerwein arylation, which
involves oxidative addition of aryl radicals derived from aryl
diazonium salts to electron-deficient alkenes using copper(I)
salts as catalysts, was first reported in 1939.9 Later it was shown
that aryl radical generation from the corresponding diazonium
salt can also be achieved with iodide, titanium(III) salts or
other metal-based reducing reagents, tetrathiafulvalene, or
photocatalysis.10,11 Heinrich and co-workers reported oxy-
arylation of alkenes with aryl diazonium salts by using a
superstoichiometric amount of an Fe(II) salt for radical
generation and the radical 2,2,6,6-tetramethylpiperidine N-
oxyl (TEMPO)12 to trap the intermediately generated adduct
radical.13 Compared with the use of aryl halides in combination
with tin hydrides for aryl radical generation,10b aryl diazonium
salts undoubtedly offer a more environment-friendly route
toward aryl radicals since toxic tin compounds are not
required.14 Moreover, aryl diazonium salts are easily prepared
from the corresponding anilines. Herein we report an
unprecedented transition-metal-free oxyarylation of alkenes
with aryl diazonium salts and TEMPONa (Scheme 1).
ABSTRACT: The reaction of readily available TEMPO-
Na with aryl diazonium salts allows for clean generation of
the corresponding aryl radicals along with TEMPO. Aryl
radical addition to alkenes with subsequent TEMPO
trapping provides the corresponding oxyarylation products
in good to excellent yields. These experimentally easy to
conduct transformations occur in the absence of any
transition metal under mild conditions, and the process
shows broad functional group compatibility.
lkenes belong to the most ubiquitous chemical feedstock,
Aand some of them are produced by industry in large scale.
Therefore, the development of chemical methods that allow for
selective alkene functionalization is an important research field
in industry as well as in academia. The Heck reaction, as one of
the most important processes for alkene arylation, has been
studied intensively during the past decades.1 In the Heck
reaction, the intermediately formed C(sp3) center generated
during the initial C−C bond-forming step is transformed into a
C(sp2) center in the ensuing β-H elimination step (Scheme 1).
Scheme 1. Alkene Arylation
We recently introduced the use of TEMPONa, which is
readily generated by reduction of commercially available
TEMPO with Na in tetrahydrofuran (THF), as a mild organic
single-electron transfer (SET) reagent for generation of the
trifluoromethyl radical from a hypervalent CF3−I(III) com-
pound.15 On the basis of these results, we envisioned that
TEMPONa could also be applied to the generation of aryl
radicals upon reaction with the corresponding aryl diazonium
salts. In the presence of an alkene, oxyarylation should be
feasible. The concept is presented in Scheme 2. TEMPONa
would first reduce the aryl diazonium salt via SET16 to generate
the corresponding aryl radical along with the persistent
TEMPO radical. Aryl radical addition to the alkene and
subsequent selective trapping of the adduct radical with
A highly valuable alternative reaction pathway would be
oxidation of the intermediately formed alkylpalladium species
(or, more generally, alkylmetal species) to give β-aryl-α-
heterofunctionalized alkanes. The initial steps in such processes
might differ from those of the typical Heck reaction (e.g., oxy-
or aminometalation of the alkene rather than carbometalation;
C−heteroatom bond formation before C−C bond formation).
Received: August 2, 2012
© XXXX American Chemical Society
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Journal of the American Chemical Society
Communication
(63−84%). Electron-donating (R = 4-OMe) and electron-
withdrawing (R = 4-CO2Me) substituents on the aryl
diazonium salt were tolerated. Moreover, bromo- and iodoaryl
diazonium salts reacted equally well, and steric effects due to
the installation of ortho substituents were negligible. To
document the practicability of our protocol, a gram-scale
experiment run with 1a and 2a afforded 3aa in 92% yield (0.93
g of 3aa was isolated).
Scheme 2. Oxyarylation of Alkenes with Aryl Diazonium
Salts and TEMPONa
Keeping aryl diazonium salt 1a as the aryl radical precursor,
we varied the aryl radical acceptor. Various styrenes 2b−n (5
equiv) bearing either electron-donating or electron-withdraw-
ing substituents were successfully converted to the correspond-
ing oxyarylation products 3ab−an in high yields (Scheme 4). In
some cases we repeated the experiment using 1.5 equiv of the
vinyl arene and found that the yield decreased only to a small
Scheme 4. Variation of the Aryl Radical Acceptor
TEMPO should eventually provide the corresponding oxy-
arylation product. The highly selective cross-coupling of the
transient adduct radical with TEMPO would be steered by the
persistent radical effect.17
Initial experiments were conducted with phenyl diazonium
salt 1a (R = H) and 5 equiv of styrene (2a) at room
temperature. TEMPONa (1.2 equiv) in THF was added by
syringe pump. The solvent and concentration were systemati-
cally varied (see the Supporting Information). Optimization
studies revealed that reaction was best conducted in α,α,α-
trifluorotoluene18 as the solvent at a concentration of 0.5 M.
TEMPONa was added over 3 h, and the oxyarylation product
3aa was isolated in 89% yield (Scheme 3). Faster or slower
Scheme 3. Variation of the Aryl Diazonium Salt
a
With 1.5 equiv of styrene.
addition of the organic SET reagent resulted in decreased
yields. Other solvents, such as MeCN (20%), ClCH2CH2Cl
(52%), and THF (69%), provided worse results. Reducing the
amount of styrene did not affect the yield to a large extent (2
equiv, 87%; 1.5 equiv, 88%). Under the optimized conditions,
various aryl diazonium salts 1b−i were reacted with 2a (5
equiv) to give the oxyarylation products 3ba−ia in good yields
a
b
With 1.5 equiv of the styrene derivative. With 10 equiv of the alkene.
c
With 3 equiv of the alkene.
B
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Journal of the American Chemical Society
Communication
extent. Surprisingly, although the yield of the CN-substituted
derivative 3ae was only slightly lower than that of the MeO
congener 3ac, we found a large difference in the relative
reactivity of the corresponding styrene derivatives. Reaction of
1a with a 1:1 mixture of 2c and 2e (5 equiv each) provided 3ac
(65%) along with traces of 3ae (<2%), showing that phenyl
radicals react highly chemoselectively with the more electron-
rich styrene derivative 2c.
To our delight, oxyphenylation also worked with non-
activated aliphatic alkenes, albeit in slightly lower yields (3aq−
au). For these less reactive acceptors, we generally used 10
equiv of the alkene. The yields were slightly lower when 3 equiv
of the radical acceptor was used (see 3at and 3au). Notably,
both terminal bromide and terminal epoxide functionalities
were compatible with the reaction conditions. Formation of
quaternary C centers was possible by using disubstituted
terminal alkenes as radical acceptors (3au and 3av). For all of
the terminal alkenes tested, the reaction occurred with
complete regioselectivity.
Radical oxyarylation worked also on internal alkenes. Hence,
the reaction of trans-β-methylstyrene with 1a provided 3aw in
53% yield with complete regioselectivity and moderate
diastereoselectivity.19 Perfect regio- and diastereoselectivity
were achieved for the transformation of 1,2-dihydronaphtha-
lene and indene (see 3ax and 3ay).
To support the mechanism suggested in Scheme 1, we
performed two control experiments. The reaction of 1a with
TEMPONa (1.2 equiv) provided TEMPO-Ph (4) in 62% yield
(eq 1), proving that a phenyl radical is formed under the
isolated in quantitative yield (99%). Oxidation of the
alkoxyamine to ketone 8 was achieved upon treatment of 3aa
with m-chloroperoxybenzoic acid (MCPBA) in CH2Cl2 (86%),
and radical deoxygenation21 occurred when the alkoxyamine
was heated in the presence of thiophenol, affording bibenzyl
(9) in quantitative yield.
In summary, we have developed a new method for transition-
metal-free radical oxyarylation of alkenes. The procedure uses
readily available aryl diazonium salts as radical precursors and
TEMPONa as a reducing reagent that upon SET is converted
to the TEMPO radical, which then acts as an oxidant in the
subsequent step. The reactions are experimentally easy to
conduct and occur under mild conditions, and the substrate
scope is broad.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
studer@uni-muenster.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the University of Munster. Y.L.
thanks the Alexander von Humboldt Foundation for support.
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D
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