Palladium-catalyzed cross-coupling of styrenes with aryl methyl ketones in ionic liquids: Direct access to cyclopropanes

Article abstract of DOI:10.1002/anie.201408245

The combined use of Pd(OAc)₂, Cu(OAc)₂, and dioxygen in molten tetrabutylammonium acetate (TBAA) promotes an unusual cyclopropanation reaction between aryl methyl ketones and styrenes. The process is a dehydrogenative cyclizing coupl

Full text of DOI:10.1002/anie.201408245

Angewandte
Chemie
DOI: 10.1002/anie.201408245
À
C H Activation
Palladium-Catalyzed Cross-Coupling of Styrenes with Aryl Methyl
Ketones in Ionic Liquids: Direct Access to Cyclopropanes**
Pietro Cotugno, Antonio Monopoli,* Francesco Ciminale, Antonella Milella, and Angelo Nacci*
Abstract: The combined use of Pd(OAc)2, Cu(OAc)2, and
dioxygen in molten tetrabutylammonium acetate (TBAA)
promotes an unusual cyclopropanation reaction between aryl
methyl ketones and styrenes. The process is a dehydrogenative
trying to develop a green and simple catalytic cyclopropana-
tion that circumvents the need for carbene (or carbenoid)
reagents by using readily available starting materials. During
our investigation of the Fujwara–Moritani (oxidative Heck)
coupling in ILs,[8,9] we found that the combined use of
Pd(OAc)2 and Cu(OAc)2 in quaternary ammonium ILs can,
under aerobic conditions, promote an unusual cyclopropana-
tion reaction between aryl methyl ketones and styrenes
(Scheme 1). This reaction can be regarded as a dehydrogen-
À
cyclizing coupling that involves a twofold C H activation at
the a-position of the ketone. The substrate scope highlights the
flexibility of the catalyst; a reaction mechanism is also
proposed.
À
C
yclopropanes are important subunits of many natural
ative cyclizing coupling involving a formal double C H
products,[1] and a large number of synthetic compounds that
carry a cyclopropane unit possess biological activities.[2] As
a consequence, great efforts have been made to develop
efficient methods for the synthesis of these small ring motifs
and to incorporate them into pharmacologically active
ingredients.[3]
activation at the a-position of the ketone, promoted by the
PdII/CuII/O2 catalyst system with the assistance of the ionic
liquid.
The most important strategies for constructing three-
membered rings start from olefins and involve the Simmons–
Smith reaction,[4] the transition-metal-catalyzed decomposi-
tion of diazo compounds,[5] and the Michael-reaction-initiated
ring closure (MIRC).[6] The first two strategies require special
reagents, such as halomethyl–zinc carbenoids or highly
reactive metal carbenes derived from copper, rhodium,
ruthenium, or cobalt catalysts. The third method involves
a sequence of a nucleophilic addition and a ring closure and
requires the presence of both electron-withdrawing and
leaving groups in the reaction partners. Nevertheless, the
synthesis of three-membered rings remains a considerable
challenge. In this context, the search for new methylene group
sources that are easier to handle and more stable than
currently used reagents, and the development of safer and
greener methods are the major issues to be addressed.
In pursuing these objectives, we exploited our previous
findings on palladium chemistry in ionic liquids (ILs),[7] in
Scheme 1. Palladium-catalyzed cyclopropanation in ionic liquid.
Preliminary investigations showed a total inhibition of the
catalysis in conventional solvents, while the reaction pro-
ceeded smoothly in molten tetrabutylammonium acetate
(TBAA) as the solvent, thus confirming the beneficial effect
that quaternary ammonium ILs often have on Pd coupling
reactions (for details see the Supporting Information).[10] In
addition, these earlier data demonstrated the need for basic
conditions, with a particularly favorable effect of acetate ions,
thus suggesting the involvement of a ketone enolate as the
intermediate.
The conditions for the cyclizing coupling were optimized
using acetophenone 1 and styrene 2 as model substrates
(Table 1). First experiments showed that the dimerization of
styrene is the main side reaction, and that the cyclopropana-
tion took place as a major pathway to afford isolated product
3 in 95% yield only when Pd(OAc)2, Cu(OAc)2, and O2 where
used together (Table 1, entries 1–3).
Air could be used in place of dioxygen, although the
reaction became significantly slower (Table 1, entry 4). The
true role played by O2 was carefully investigated by measur-
ing the gas volume consumed during the reaction (gas
burette). The requirement of a 2:1 stoichiometric ratio of
acetophenone to O2 clearly indicated that molecular oxygen
acts as the terminal oxidant, affording H2O as by-product
(Figure 1). Moreover, XPS analyses of the reaction mixture
showed that at the end of the process negligible amounts of
Cu0 and CuI were detected together with CuII (see the
[*] Dr. P. Cotugno, Dr. A. Monopoli, Prof. F. Ciminale, Dr. A. Milella,
Prof. A. Nacci
Department of Chemistry, University of Bari
Via Orabona 4, 70126 Bari (Italy)
E-mail: antonio.monopoli@uniba.it
angelo.nacci@uniba.it
Prof. A. Nacci
CNR-ICCOM, Department of Chemistry, University of Bari
Via Orabona 4, 70126 Bari (Italy)
[**] We thank the University of Bari, the Italian Ministry of Instruction,
University and Research (MIUR), and the Regione Puglia (“PON
Ricerca e Competitivitꢀ” 2007–2013—Avv. 254/Ric. del 18/05/2011,
Project PONa3 00369 “Laboratorio SISTEMA”) for financial sup-
port.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408245.
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Table 1: Optimization of reaction conditions.[a]
The investigation of the substrate scope revealed a pro-
found influence of the ketone skeleton on the reaction
outcome. Indeed, the simultaneous presence of two poten-
tially active metals opened the way to a plethora of processes
with either Pd or Cu (or both) behaving as active catalysts.
Table 2 summarizes the major processes promoted in the
ionic medium, thus indicating the true operating catalyst.
It is noteworthy that aryl ketones were the most reactive
substrates, and among them acetophenone 1 was unique in
affording the cyclopropanation product 3, requiring the
simultaneous presence of PdII, CuII, and O2 (Table 2, entries 1
and 2). Other aryl ketones underwent different reactions,
depending on both the reaction conditions and the degree of
substitution at the a-position of the carbonyl group. For
example, propiophenone (Table 1, entries 3 and 4) was
predominantly converted into the self-condensed diketone
4, most likely through three PdII-mediated consecutive steps
Entry
Pd cat.
Reoxidant
Gas
t
[h]
Conv.
[%][b]
Sel.
[%][c]
1
2
3
4
5
6
7
8
–
Cu(OAc)2
–
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Riboflavin
benzoquinone
K2S2O8
FeCl3
AgOAc
CuSO4
Cu(TfO)2
CuOAc
O2
O2
O2
air
O2
air
air
air
O2
O2
O2
O2
O2
O2
O2
O2
2
2
2
6
10
2
6
6
2
2
2
6
2
2
2
2
0
0
0[d]
0[d]
100
100
100
–
–
–
–
–
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
>99(95)
98
15
0
0
0
[e]
9
0
0
10
11
12
13
14
15
16
52
0
67
>99
0
100
[d]
–
À
involving C H activation/b-hydride elimination/Michael
100
55[f]
–
addition (Scheme 2a).[14] This might represent a useful mech-
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Pd(dba)2
Pdnanopart.
À
anistic suggestion, as the preliminary C H activation step can
0
–
[a] Reaction conditions: TBAA (0.2 g), 1 (0.25 mmol), 2 (0.25 mmol),
Pd(OAc)2 (5 mol%), and reoxidant (1 equiv) heated at 1008C under O2
(or air) atmosphere (1 atm). In all cases, 3 was obtained in a trans/cis
ratio higher than 99:1. [b] With regard to 1, evaluated by GC-MS (in
brackets isolated yields of 3). [c] Based on the ratio of GLC peak areas of
3 to by-products. [d] Only styrene dimerization products were observed.
[e] With 0.2 equiv of Cu(OAc)2. [f] Oxidative dimerization of styrene was
observed (1,4-diphenyl-1,3-butadiene obtained in 45% yield).
Supporting Information), thus suggesting that Cu(OAc)2 is
simply involved as an electron-transfer mediator in the
reoxidation of Pd0 by the terminal oxidizing agent O2.[11]
Concerning the role of copper, it is important to point out
that direct reoxidation with O2 is feasible, but this reaction
was found to be very slow in the ionic medium in the absence
of CuII.[12] This could explain the requirement for equimolar
amounts of Cu(AcO)2 for a complete conversion into cyclo-
propane (Table 1, entry 5).[13] However, the total inefficacy of
other oxidants commonly used in Pd-catalyzed oxidative
couplings (Table 1, entries 6–10) suggested another role of
CuII in the catalytic cycle. In the absence of more direct
evidence, one could speculate that Cu2+ might also assist in
the nucleopalladation of styrene by the PdII enolate inter-
mediate A through a preliminary p-coordination of the
double bond (see Figure 1). Other copper(II) sources, such as
CuSO4 and Cu(OTf)2, were also tested, but with disappointing
results. This confirms the beneficial effect of the acetate anion
(Table 1, entries 11 and 12). As expected, CuIOAc exhibited
fairly good activity, but required an induction period because
of the necessary preliminary oxidation of CuI to the active
species CuII (Table 1, entry 13). The preliminary screening
was completed by the investigation of some other Pd sources.
PdCl2 provided unsatisfactory results in terms of selectivity
(Table 1, entry 14), while Pd0 catalysts, such as [Pd(dba)2] and
preformed Pd0 nanoparticles, were completely inefficient,
thus indicating that PdII is the catalytically active species
(Table 1, entries 15 and 16).
Scheme 2. Plausible pathways for reactions of aryl ketones.
be assumed to also occur for acetophenone, whose enolate,
which is not compatible with a b-H elimination, would evolve
in a different way, giving oxa-p-allylpalladium A and then
resulting in the cyclopropanation process (Figure 1). In
contrast, the presence of a tertiary carbon atom at the a-
position of isobutyrophenone opened the way to known a-
alkylation reactions (promoted exclusively by CuII), the
outcome of which was dependent on the presence of O2
(Table 2, entries 5 and 6). Indeed, under inert atmosphere,
the simple addition of the ketone enolate to styrene was
observed with the formation of adduct 5.[15] On the contrary,
under oxygen atmosphere, a radical pathway was initiated by
a single-electron oxidation of the same enolate moiety
followed by a cyclizing step that led to the dihydronaphtha-
len-1-one 6[16] (Scheme 2b and Table 2, entry 6). Different
results were obtained with 1,2-diphenylethanone, which bears
2
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Table 2: Substrate scope.[a]
oxa-p-allylpalladium complex A.
With regard to reports suggesting
the possible formation of oxa-p-
allylpalladium intermediates,[19] we
gained direct evidence of the for-
mation of A by monitoring the
reaction mixture by ESI-HRMS
(Figure S3). The addition to styrene
(Markovnikovꢀs rule) should afford
the intermediate B, in which the
proton abstraction from the g-posi-
tion leads to the formation of a new
Entry Ketone
Gas Major
Conv. Operating Promoted
[%][b] catalyst[c] process
product
1
2
N2
O2
<5
–
cyclo-
propanation
>99 PdII/CuII
3
4
O2
N2
90
dehydrogenation/
Michael reaction
PdII
85
5
6
N2
O2
88
96
CuII[d]
oxa-p-allylpalladium complex
C
a-alkylation
(releasing acetic acid). Reductive
elimination from C provides the
cyclopropane ring and Pd0, which
is then reoxidized to the PdII cata-
lyst by molecular O2 (with the
assistance of Cu2+). The g-selectiv-
ity governing the hydrogen abstrac-
tion on intermediate B represents
the key feature of the whole pro-
cess. The reason for such a selectiv-
ity could be found not only in the
higher acidity of protons in that
position, but also in the chelating
structure of B that should impede
palladium to reach the syn co-pla-
narity with the b-hydrogen to result
in b-H elimination. In addition, the
g-deprotonation could occur intra-
molecularly by coordination of the
CuII[d]
a-oxidative
homocoupling
7
8
N2
O2
20
95
CuII[d]
CuII[d]
–
a-oxygenation
–
9
10
N2
O2
0
0
–
11
12
N2
O2
100
100
PdII
dehydrogenation
13
14
15
16
N2
O2
N2
O2
0
50
0
–
dehydrogenation
isomerization
PdII
mixture of octene isomers
PdII
0
[a] Reaction conditions: TBAA (0.2 g), ketone (0.25 mmol), styrene (0.25 mmol), Pd(OAc)2 (5 mol%),
Cu(OAc)2 (0.25 mmol) heated at 1008C under O2 (or N2) atmosphoere (1 atm). [b] With regard to the
starting ketone, evaluated by GLC. [c] As deduced from appropriate catalytic tests carried out by using
the two metals separately. [d] Reaction proceeds also with 20 mol% of Cu(OAc)2 alone.
a benzylic carbon atom at the a-position to the carbonyl
group (Table 2, entries 7 and 8). In this case, the formation of
a stable a-carbonylbenzyl radical promoted by copper
accounts for the observed transformations: the oxidative
homo-coupling to 1,4-dione 7[17] under inert atmosphere, or
the a-oxygenation reaction to benzil 8[18] (Scheme 2c and
Table 2, entries 7 and 8).
Aliphatic ketones were almost unreactive or underwent
unproductive side reactions, thus indicating that the presence
of an aromatic ring linked to the carbonyl group is essential
for the coupling with styrene. Indeed, pinacolone was
completely inert under the various conditions (Table 2,
entries 9 and 10), while 2-heptanone underwent a PdII-
promoted b-H elimination,[10b,14] affording a complex mixture
of polyunsaturated heptanones (Table 2, entries 11 and 12). In
a similar manner, cyclohexanone was partially dehydrogen-
ated to phenol in the presence of dioxygen[14b] (Table 2,
entries 13 and 14). Finally, terminal aliphatic alkenes proved
Figure 1. The plausible cyclopropanation mechanism.
to be useless reactants that were converted to a complex
mixture of alkenes with isomerized double bonds under the
conditions (Table 2, entries 15 and 16), while internal alkenes
were completely unreactive.
acetate anion to Pd, which could explain the need for the
presence of AcOÀ as a counterion of both the PdII source and
ionic liquid medium. Any alternative radical mechanism
could be ruled out by appropriate experiments involving the
addition of TEMPO or BHT, which did not noticeably affect
the reaction.
Based on these findings, we proposed the reaction
mechanism depicted in Figure 1 for the cyclopropanation.
The cycle is initiated by PdII which gives rise to the C H
À
activation at the a-position of acetophenone, leading to the
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Table 3: Synthesis of aryl(2-arylcyclopropyl)methanones.[a]
3, 95%
9, 70%
10, 72%
13, 92%
11, 75%
12, 93%
14, 92%
17, 94%
15, 87%
18, 89%
16, 50%
19, 83%
Scheme 3. Synthesis of the antimalarial compound 23. a) KOH, EtOH,
RT; b) TMSOI, TBAB, NaOH, 808C; c) Me2NH, K2CO3, DMF, 1208C.
DMF=N,N-dimethylformamide. TBAB=tetrabutylammonium bro-
mide, TMSOI=trimethylsulphoxonium iodide.
20, 77%
21, 87%
22, 85%
with long aliphatic chains because of reactions that lead to
dehydrogenated by-products. Studies are in progress to
further confirm the mechanism and ascertain the exact role
of copper and the ionic liquid.
[a] Reaction conditions: TBAA (0.2 g), aryl ketone (0.25 mmol), olefin
(0.25 mmol), Pd(OAc)2 (5 mol%), and Cu(OAc)2 (0.25 mmol) heated at
1008C for 2–8 h under O2. All reported yields are of isolated products.
Cyclopropanes were always obtained in a trans/cis ratio higher than 98:2.
Received: August 14, 2014
Published online: && &&, &&&&
With these results in hand, we extended the substrate
scope to an array of substituted aryl methyl ketones and
styrenes. The results in Table 3 show that the catalyst system
exhibits good activity on these substrates, affording aryl(2-
arylcyclopropyl)methanones 3 and 9–22 in moderate to
excellent yields. It is noteworthy that only a little influence
of the nature of substituents on the catalyst activity was
observed, with an expected beneficial effect exerted by
electron-withdrawing groups.
À
Keywords: C H activation · copper · cyclopropanation ·
ionic liquids · palladium
.
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À
and styrenes proceeding through a double C H activation at
the a-position of a ketone. The practical advantages of this
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free conditions, relatively mild temperatures (1008C), molec-
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product. A limitation of this method resides in the structures
of the substrates, which may not include ketones and alkenes
4
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Communications
À
C H Activation
P. Cotugno, A. Monopoli,* F. Ciminale,
A. Milella, A. Nacci*
&&&& — &&&&
Palladium-Catalyzed Cross-Coupling of
Styrenes with Aryl Methyl Ketones in Ionic
Liquids: Direct Access to Cyclopropanes
Double activation: The combined use of
Pd(OAc)2, Cu(OAc)2, and dioxygen in
molten tetrabutylammonium acetate
(TBAA) promotes an unusual cyclopro-
panation reaction between aryl methyl
ketones and styrenes. The process is
a dehydrogenative cyclizing coupling that
À
involves a twofold C H activation at the
a-position of the ketone.
6
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