Acid-catalyzed oxidative radical addition of ketones to olefins

Article abstract of DOI:10.1002/anie.201401062

Based on a mechanistic study, we have discovered a Bronsted acid catalyzed formation of ketone radicals. This is believed to proceed via thermally labile alkenyl peroxides formed in situ from ketones and hydroperoxides. The discovery could be utilized to develop a multicomponent radical addition of unactivated ketones and tert-butyl hydroperoxide to olefins. The resulting γ-peroxyketones are synthetically useful intermediates that can be further transformed into 1,4-diketones, homoaldol products, and alkyl ketones. A one-pot reaction yielding a pharmaceutically active pyrrole is also described.

Full text of DOI:10.1002/anie.201401062

Angewandte
Chemie
DOI: 10.1002/anie.201401062
Synthetic Methods
Acid-Catalyzed Oxidative Radical Addition of Ketones to Olefins**
Bertrand Schweitzer-Chaput, Joachim Demaerel, Hauke Engler, and Martin Klussmann*
Dedicated to the MPI fꢀr Kohlenforschung on the occasion of its centenary
Table 1: Initial discovery and optimization of reaction conditions.[a]
Abstract: Based on a mechanistic study, we have discovered
a Brønsted acid catalyzed formation of ketone radicals. This is
believed to proceed via thermally labile alkenyl peroxides
formed in situ from ketones and hydroperoxides. The discov-
ery could be utilized to develop a multicomponent radical
addition of unactivated ketones and tert-butyl hydroperoxide
to olefins. The resulting g-peroxyketones are synthetically
useful intermediates that can be further transformed into 1,4-
diketones, homoaldol products, and alkyl ketones. A one-pot
reaction yielding a pharmaceutically active pyrrole is also
described.
Entry Solvent T [8C] Catalyst [mol%] Equiv. tBuOOH Yield [%][b]
1
2
3
4
5
6
7
8
acetone
acetone
acetone
acetone
acetone
acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
40
60
60
60
60
60
60
60
60
50
50
MsOH (7)
MsOH (10)
TFA (10)
2
4
4
4
4
4
4
3
5
4
4
43
55
9
55
53
57
58
48
H2SO4 (10)
HNO3 (10)
pTsOH (10)
pTsOH (10)
pTsOH (10)
pTsOH (10)
pTsOH (10)
pTsOH (2)
D
uring our mechanistic investigation of the autoxidative
coupling of xanthene with ketones,[1] we discovered an
intriguing formation of radicals from ketones and hydro-
peroxides, catalyzed by a strong Brønsted acid without
involvement of a redox-active catalyst.[2] However, the
mechanism of radical formation and their actual structure
was not fully understood. Here we present results supporting
the formation of ketone-derived radicals via intermediate
alkenyl peroxides which enable a Brønsted acid catalyzed
difunctionalization of styrenes.
9
10
11
58
74 (74)[c]
77 (76)[c]
[a] Styrene (0.5 mmol), acetone (2.5 mmol), tBuOOH (5.5m solution in
decane), acid (0.05 mmol), solvent (2 mL), reaction overnight (ca. 16 h).
[b] Yield determined by NMR analysis using an internal standard, yield of
isolated product in parentheses. [c] Degassed, under argon.
We chose the combination of acetone and tert-butyl
hydroperoxide (in decane solution) together with catalytic
amounts of methanesulfonic acid at 408C from our previous
studies,[2] and added styrene in order to isolate potential
trapping products. From this experiment, we could isolate
compound 1 in 43% yield (Table 1, entry 1). This strongly
suggests the formation of a carbon-centered radical at the a-
position of acetone, which added to the styrene double bond
and subsequently formed 1.
The carbofunctionalization of olefins represents an attrac-
tive strategy to rapidly build complex molecules from simple
starting materials.[3] The addition of ketone-derived radicals
to olefins has been reported by Kharasch using UV light[4] and
was investigated with various other initiation methods since
then, generally resulting in hydroalkylation products.[5,6]
Cases of oxyalkylations as seen in product 1 can be achieved
by using Mn compounds as catalyst and/or oxidant but are
much less common.[6c,f,g,7] The direct formation of 1,4-dike-
tones can be achieved by combined copper and organo-
catalysis using MnO2 as an oxidant.[7] As an alternative to free
ketones, ester enolates and enamines can be converted to the
corresponding radicals by single-electron-transfer reagents.[8]
The related radical addition of 1,3-dicarbonyl compounds
to olefins has been more thoroughly investigated,[5,9] as is also
the case with alkylations[10] and acylations[11] using aldehydes.
The concept of SOMO catalysis[12] enables the asymmetric
carbofunctionalization of olefins with aldehydes.[10] Notewor-
thy and complementary reactions in this context are the
metal-catalyzed formations of peroxides similar to 1 from 1,3-
dicarbonyl compounds[9i] and aldehydes.[11d,g]
Since the formation of 1 is unique from a mechanistic as
well as synthetic perspective and little is known about the
synthetic utility of such compounds,[9i] we decided to inves-
tigate this reaction in more detail (see Table 1 and the
Supporting Information for further details).
Because 1 was found to be stable under reaction
conditions, all reactions were performed overnight to ensure
complete conversion of tBuOOH. Increasing the amount of
oxidant as well as increasing the temperature to 608C
improved the yield (Table 1, entry 2). Different Brønsted
acids were tested and we found that strong acids have to be
used: trifluoroacetic acid (TFA) only gives 9% yield (Table 1,
entry 3), while nitric, sulfuric, and sulfonic acids all gave
[*] B. Schweitzer-Chaput, J. Demaerel, H. Engler, Dr. M. Klussmann
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45479 Mꢀlheim an der Ruhr (Germany)
E-mail: klusi@mpi-muelheim.mpg.de
Homepage: http.//www.kofo.mpg.de
[**] Financial support from the DFG (Heisenberg scholarship to M.K.,
KL 2221/4-1; KL 2221/3-1), the MPI fꢀr Kohlenforschung, and Prof.
Benjamin List is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201401062.
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similar yields of 53–57% (Table 1, entries 4–6), with para-
toluenesulfonic acid (pTsOH) being the most effective
(Table 1, entry 6, 57%). In the absence of acid, 1 was not
detected. Some Lewis acids were also found to be suitable
catalysts, but Fe and Cu salts—common redox catalysts—
failed completely. When acetonitrile was used as a cosolvent,
the amount of ketone substrate could be reduced, with
5 equivalents being optimal (Table 1, entries 6 and 7). Sim-
ilarly, an excess of 4 equivalents of tBuOOH gave the best
product yields (Table 1, entries 7–9). Reducing the temper-
ature to 508C proved to be beneficial, as well as performing
the reactions with strict exclusion of oxygen (Table 1,
entry 10). Reducing the acid loading from 10 to 2 mol%
resulted in a longer reaction time but essentially unchanged
yield (Table 1, entry 11). Since this was not general for all
ketones, we used 10 mol% catalyst loading to study the
ketone substrate scope (Scheme 1).
tuted acetophenone (7b, 37%), and an electron-donating
methoxy group was beneficial (7c, 44%). Cyclopentanone
and cyclohexanone gave good yields of products 8 and 9 (60%
and 62%, respectively). Acetyl acetone selectively gave
product 10 in 62% yield as the only isomer. Similarly,
methyl acetoacetate gave 11 in a yield of 56%. Dimethyl
malonate—a successful substrate type in metal-catalyzed
reactions[5]—proved to be unreactive under these conditions.
The olefin scope was explored using acetone as a standard
coupling partner and an acid loading of 2 mol% (Scheme 2).
Halogen-substituted styrenes were well tolerated and gave
the corresponding products 12a–c in good yields of 57% to
64%. Substrates with a strongly electron-withdrawing cyano
substituent as well as with a methyl group showed similar
reactivities and the corresponding products 12d and 12e were
Scheme 2. Substrat scope for the reaction of acetone with various
styrenes or other olefins. [a] Acetone as solvent, 408C, 10% acid
loading.
Scheme 1. Substrate scope for the reaction of ketones with styrene.
Going from primary over secondary to tertiary ketones,
a major drop in reactivity is observed. Acetone gives a 74%
yield of product 1, diethyl ketone afforded product 2 in 47%
yield, while diisopropyl ketone led to only traces of product 3.
This lack of reactivity could be due to steric effects. An
asymmetric ketone like butanone showed a preference for
radical formation at the primary carbon, giving 66% yield of
product 4 as a mixture with a ratio of about 2:1 in favor of the
linear isomer 4a. In the reaction of 3-methyl-2-butanone, in
which both primary and tertiary carbons are available, 5 was
isolated in 68% yield as the only product, showing perfect
selectivity for the primary carbon. Pinacolone gave a good
75% yield of product 6. Substituted acetophenones were used
to probe electronic effects. An electron-withdrawing group
reduced the yield (7a, 18%) relative to that with unsubsti-
isolated in 57% and 59% yield, respectively. By contrast,
a strongly electron-donating methoxy group led to a sharp
reduction of yield and only traces of product 12 f could be
isolated. This is mainly attributed to the instability of 12 f
under the reaction conditions: when the reaction was
performed in acetone at slightly lower temperature (408C),
12 f could be isolated in 33% yield. 2,4,6-Trimethylstyrene,
which combines electron-donating groups and steric hin-
drance, gave product 13 in a low yield of 26%. Vinyl
naphthalene gave a lower yield than styrene, providing 14 in
52% yield. 2-Bromostyrene, having a bulky substituent close
to the reactive site, similarly gave a moderate 39% yield of 15.
Tertiary peroxides could also be accessed, as shown by the
reactions of a-methylstyrene (product 16, 56%) and 1,1-
diphenylethylene (product 17, 68%).
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trans-Stilbene gave a 61% yield of product 18 as a 2:1
mixture of diastereomers. cis-Stilbene gave an identical
mixture but in a much lower yield of 21%. Cyclic substrates
such as 1-phenylcyclohexene (19, 27%), indene (20, 59%),
and dihydronaphthalene (21, 47%) could be used success-
fully. Preliminary studies show that the reaction is not limited
to styrenes: trans-dibenzoylethylene and allyl benzene pro-
vided the g-peroxyketones 22 and 23 in 47% and 12% yield,
respectively. The low yield of 23 suggests that a resonance-
stabilizing group on the olefin is beneficial. Vinyl pyridines
were completely unreactive, most likely because these basic
substrates deactivate the acid catalyst.
Further synthetic transformations of the g-peroxyketone
products were investigated with 1 as a model substrate
(Scheme 3a). In the presence of a catalytic amount of base
Scheme 4. Suggested mechanism of product formation.
the presence of a strong acid, tBuOOH adds to the ketone to
form 30 and subsequently alkenylperoxide 31. Such com-
pounds are reported to undergo facile homolytic bond
cleavage,[17c,d] which would generate the resonance-stabilized
ketone radical 32 and a tert-butoxyl radical 33. In the presence
of tBuOOH, a fast equilibrium exists between 33 and the tert-
butylperoxyl radical 34, favoring the latter.[17a] Addition of 32
to the styrene double bond would form 35, which reacts with
the peroxy radical 34 to give the final product 1. The selective
cross-coupling of 35 with 34 can be explained by the
“persistent radical” effect,[18] in that 34 is a persistent
radical[18b] and 35 a transient radical.
The observed selectivity for the linear versus branched
product (4a vs. 4b) could be explained by the rapid
decomposition of alkenylperoxides like 31, which gives the
less substituted ketone radical rather than the thermodynami-
cally preferred one owing to kinetic preferences. The
observations that Fe and Cu salts fail as catalysts and that
dimethyl malonate fails as a carbonyl component are both in
agreement with the proposed mechanism. Fe and Cu salts are
known catalysts for the decomposition of tBuOOH to
radicals, which can mediate reactions by hydrogen-atom
transfer (HAT) or by single-electron transfer (SET).[17a,19]
Also, the radical addition of activated methylene compounds
to olefins can be initiated by SET or HAT.[5,9] Accordingly, it
appears that neither SET nor HAT is operative in the present
system but rather the ketone radicals are formed directly. The
presence of Fe and Cu salts could shut down the formation of
30 and 31 by fast decomposition of tBuOOH while a malonate
could be too unreactive for the formation of ketene perketals
analogous to 31 under reaction conditions.
In conclusion, we have developed a multicomponent
alkylation–peroxidation reaction of styrene derivatives with
ketones by Brønsted acid catalysis, based on a previous
mechanistic study. The g-peroxyketone products thus
obtained can be further converted to synthetically useful
1,4-diketones, homoaldol products, and alkyl ketones. The
reaction is thus a valuable addition to the mostly metal-
mediated addition reactions employing activated methylene
compounds, which are less effective with simple ketones. The
mechanistic information gained by this study sheds further
light on the autoxidative coupling reaction with xanthene[1,2]
and could be useful for future developments.
Scheme 3. Further transformations of the g-peroxyketone products.
(Kornblum–DelaMare rearrangement[13]), 1 can be trans-
formed into the corresponding 1,4-diketone 24, an important
class of intermediates in the synthesis of heterocycles such as
pyrroles[14] and furans.[15] When 1 is hydrogenated using
palladium on carbon in acetonitrile, the corresponding
homoaldol product 25 is obtained. When the hydrogenation
is performed in methanol, complete reduction of the benzylic
position is observed, giving product 26. The reaction proceeds
via acetal 27, which can be isolated if the reaction is not
allowed to run to completion. The direct acid-catalyzed
transformation of 1,3-diketo-g-peroxides to furans has been
reported.[9i]
Finally, a one-pot synthesis of pyrrole 28, a nonsteroidal
antiinflammatory agent,[16] was performed (Scheme 3b). The
reaction of styrene and cyclohexanone as depicted in
Scheme 1 resulted in the formation of peroxide 9, which
was directly converted to the corresponding diketone by
adding one equivalent of DBU to the reaction mixture. After
removing acetonitrile, we followed the reported procedure[16]
and added aniline 29 together with acetic acid and heated the
mixture at reflux. Pyrrole 28 was obtained in 30% yield over
three steps using a single purification step and in 41% yield if
each product was purified before the next step.
Consistent with these results and previous investiga-
tions,[2,17] a plausible mechanism is shown in Scheme 4. In
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Received: January 31, 2014
Published online: && &&, &&&&
Keywords: ketones · multicomponent reactions ·
.
organocatalysis · peroxides · radicals
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Communications
Synthetic Methods
B. Schweitzer-Chaput, J. Demaerel,
H. Engler,
M. Klussmann*
&&&& — &&&&
Acid-Catalyzed Oxidative Radical
Addition of Ketones to Olefins
A radical combination: A multicompo-
nent radical addition of unactivated
ketones and hydroperoxide to styrenes
under Brønsted acid catalysis provides
a range of g-peroxyketones. The products
can be further transformed into 1,4-
diketones, homoaldol compounds, and
alkyl ketones. The formation of radicals is
believed to proceed via thermally labile
alkenylperoxides, which are generated in
situ.
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