Ruthenium-catalyzed hydroaroylation of styrenes in water through directed C-H bond activation

Article abstract of DOI:10.1002/cctc.201402031

Selective C-H bond-functionalization reactions of arenes offer the potential for a more benign synthesis of fine chemicals and organic building blocks for the life science industries. In this respect, direct carbonylative coupling reactions of (hetero)arenes allow for the straightforward synthesis of (hetero)aromatic ketones and related derivatives. Herein, we present an efficient ruthenium(II)-catalyzed carbonylative hydroarylation of alkenes through directed C-H functionalization. More specifically, the carbonylative hydroarylation of styrenes with 2-aryl- (heteroaryl)pyridines and related derivatives proceeds selectively and with 100 % atom efficiency in water as the solvent. Three-Component Hydroaroylation: Hydroaroylation through C-H activation of (hetero)arenes bearing ortho-directing groups (DGs) proceeds in the presence of a ruthenium catalyst, carbon monoxide, and styrenes. The shown coupling process provides selective and atom-economic access to (hetero)- aromatic ketones.

Full text of DOI:10.1002/cctc.201402031

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DOI: 10.1002/cctc.201402031
Ruthenium-Catalyzed Hydroaroylation of Styrenes in
Water through Directed CÀH Bond Activation
Anis Tlili, Johannes Schranck, Jola Pospech, Helfried Neumann, and Matthias Beller*[a]
Selective CÀH bond-functionalization reactions of arenes offer
the potential for a more benign synthesis of fine chemicals
and organic building blocks for the life science industries. In
this respect, direct carbonylative coupling reactions of (hetero)-
arenes allow for the straightforward synthesis of (hetero)aro-
matic ketones and related derivatives. Herein, we present an
efficient ruthenium(II)-catalyzed carbonylative hydroarylation of
alkenes through directed CÀH functionalization. More specifi-
cally, the carbonylative hydroarylation of styrenes with 2-aryl-
(heteroaryl)pyridines and related derivatives proceeds selec-
tively and with 100% atom efficiency in water as the solvent.
Scheme 1. Carbonylative three-component CÀC coupling reactions.
On the basis of the development of organometallic coupling
reactions, the transition-metal-catalyzed construction of CÀC
and CÀheteroatom bonds of aryl halides and related substrates
is nowadays routinely applied for all kinds of organic synthe-
ses. Without doubt, these methodologies provide an efficient
tool box for both basic research as well as for the industrial
production of fine chemicals on the ton scale.[1] However, the
inherent problem of salt-waste formation as well as the neces-
sity for additional prefunctionalization steps generates interest
to develop more straightforward and greener processes. Thus,
in the last decade several novel coupling reactions making use
of the direct functionalization of CÀH bonds have been dis-
closed.[2] As catalysts, ruthenium complexes exhibit a unique
activation mechanism for these processes and have enabled
significant progress in cross-coupling reactions including
C(sp2)ÀH bond activation.[3] Although interesting ruthenium-
catalyzed hydroarylations were initially developed,[4,5] related
hydroaroylations leading to ketones by additionally incorporat-
ing a molecule of carbon monoxide have been studied less. In
general, for the latter reactions harsh reaction conditions are
required (up to 1808C), and known protocols are basically lim-
ited to the functionalization of imidazole derivatives or to the
use of (a large excess amount of) ethylene as the coupling
partner.[6,7]
three-component coupling of alkenes, carbon monoxide, and
(hetero)arenes bearing ortho-directing groups to give the cor-
responding alkyl aryl ketones (Scheme 1).
Notably, such ketones can also be obtained through inter-
molecular hydroacylation reactions;[10] however, presynthesis of
the corresponding aldehydes is required. In addition, cross-de-
hydrogenative-coupling provides alternative access to these
products. In this latter case, the requirement of (over)stoichio-
metric amounts of an oxidant is a drawback.[11] Finally, it is
worth mentioning that classical three-component carbonyla-
tive processes in the presence of (over)stoichiometric amounts
of organometallic coupling reagents also allow for the synthe-
sis of similar ketones.[12]
Our initial catalytic experiments were performed with 2-phe-
nylpyridine and styrene as model substrates in the presence of
[Ru(cod)Cl2] (5 mol%, cod=1,5-cyclooctadiene) polymer at
a medium pressure (3 MPa) of carbon monoxide. The testing
of different solvents showed their crucial influence on this re-
action. Employing common polar and nonpolar organic sol-
vents such as DMSO, DMF, N-methylpyrrolidone (NMP), tolu-
ene, MeCN, and 1-propanol did not result in any conversion of
the starting material (Table 1, entries 1–7). However, changing
the solvent to water induced a significant increase in reactivity,
which is in agreement with other Ru-catalyzed coupling reac-
tions.[13] Gratifyingly, the desired 3-phenyl-1-[2-(pyridin-2-yl)-
phenyl]propan-1-one was obtained in water in 73% yield
(Table 1, entry 7). The reaction proceeded highly selective to-
wards the mono-hydroaroylation product and no trace
amounts of the direct hydroarylation product or the double
hydroarylation product were observed. Nevertheless, trace
amounts of side products derived from the hydroformylation
and reduction of styrene were observed.
On the basis of our interest in carbonylation reactions[8] and
the recent development of selective Ru-catalyzed aroylations
of (hetero)arenes,[9] herein we report a general and selective
[a] A. Tlili,+ J. Schranck,+ J. Pospech, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
To improve the carbonylative coupling process further, we
investigated the effect of different additives. Recently, Acker-
mann and co-workers demonstrated that the addition of cata-
lytic amounts of carboxylates enhanced the reactivity of Ru
Homepage: www.catalysis.de
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402031.
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Table 1. Ruthenium-catalyzed carbonylative CÀH activation of 2-phenyl-
Table 2. Ruthenium-catalyzed hydroaroylation through CÀH activation:
pyridine: Variation of the reaction conditions.[a]
Substrate scope with different aryl styrenes.[a]
Entry
1
Styrene
Product
Yield[b] [%]
65
Entry
Solvent
(1 mL)
[Ru]
(5 mol%)
Additive
(0.2 equiv.)
Yield[b]
[%]
1a
1b
1c
1d
1e
1 f
1
2
3
4
5
6
7
8
DMSO
DMF
NMP
PhMe
MeCN
1-propanol
H2O
H2O
H2O
H2O
H2O
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(cod)]n
[RuCl2(p-cymene)]2
CpRuCl(PPh3)2
Ru(acac)3
–
–
–
–
–
–
–
0
0
0
0
0
0
2
3
4
5
6
69
52
74
64
44
73 (64)[c]
KOAc
HOAc
CHOONa
52
44
24
18
67
0
13
9
10
11
12
13
14
15
16
[d]
AgSbF6
H2O
H2O
H2O
H2O
–
–
–
–
–
[RuCl2(cod)]n
–
41,[e] 63[f]
0
H2O
[a] Reactions were performed with styrene (5 mmol), 2-phenylpyridine
(0.5 mmol), ruthenium complex (5 mol%), and additive (0.2 equiv.) under
carbon monoxide pressure (3 MPa) at 1308C for 24 h unless otherwise
noted; Cp=cyclopentadienyl. [b] Calibrated yield was obtained by GC by
using hexadecane as an internal standard; average of two runs. [c] Yield
of isolated product is given in parentheses. [d] AgSbF6 (10 mol%) was
used. [e] Reaction was performed at 1208C. [f] Reaction was performed
with CO (2 MPa).
7
1g
1h
1i
64
68
38
44
8
9
catalysts in CÀH functionalization reactions by facilitating the
formation of the cyclometalated ruthenium intermediate.[5a]
However, under our reaction conditions, the addition of potas-
sium acetate (20 mol%) did not improve the reactivity or selec-
tivity and even lowered the product yield (Table 1, entry 8). We
assume that water could assist CÀH bond cleavage and the
subsequent formation of the cyclometalated ruthenium com-
plex. The same trend was observed if the reaction was per-
formed in the presence of acetic acid or sodium formate
(Table 1, entries 9 and 10). Also, attempts to improve the reac-
tivity by in situ formation of a cationic ruthenium complex
through the addition of AgSbF6 led to a poor product yield
(Table 1, entry 11). Among the tested Ru complexes, the
dichloro(p-cymene)ruthenium(II) dimer enabled a good yield of
the desired product, although it was lower than that obtained
withe the use of the [Ru(cod)Cl2] polymer (Table 1, entries 12–
14; acac=acetylacetonate). Decreasing the carbon monoxide
pressure to 2 MPa lowered the product yield slightly to 63%,
whereas applying a lower temperature (1208C) caused a stron-
ger decrease in the formation of the product to 41% (Table 1,
entry 15). No product formation was observed in a blank ex-
periment (Table 1, entry 16).
10
1j
11
1k
78
[a] Reactions were performed with styrene (5 mmol), 2-phenylpyridine
(0.5 mmol), and ruthenium complex (5 mol%) under carbon monoxide
pressure (3 MPa) at 1308C for 24 h. [b] Yield of isolated product.
using [RuCl2(cod)]n in H2O (Table 2). Styrenes bearing either
electron-donating (Table 2, entries 1–4) or electron-withdraw-
ing groups (Table 2, entries 6–11) gave the corresponding
ketone derivatives in moderate to very good yields (38–78%).
No general trend was observed if the styrene was substituted
in the ortho-, meta-, or para position. Interestingly, pentafluor-
ostyrene led to the corresponding product 1h in good yield
(Table 2, entry 8). In general, excellent chemoselectivity with re-
spect to phenylpyridine was observed. However, the use of an
With the optimized conditions in hand, we examined the
carbonylation of 2-phenylpyridine with different styrenes by
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Furthermore, we investigated the application of
other vinyl compounds. Thereby, vinyltrimethylsilane
was successfully converted into product 11 h and iso-
lated in 58% yield [Scheme 4, Eq. (1)]. Starting the re-
action with 1-allyl-4-fluorobenzene was also effective
under the standard reaction conditions and led to
the isolation of two regioisomers, 12h and 13h, in
moderate yields [Scheme 4, Eq. (2)].
To shed some light on the mechanism of our hy-
droaroylation reaction,[15] H/D exchange experiments
were performed. If the carbonylative reaction was
performed either starting from deuterated 2-phenyl-
pyridine or with the use of deuterated water as the
solvent, H/D exchange was observed after 24 h
[Scheme 5, Eqs. (1) and (2)]. These results confirm the
reversibility of the metalation step. Interestingly,
a second H/D exchange in the b-position of the car-
bonyl group was detected to a significant extend
1
(54%) by H NMR spectroscopy if the reaction of 2-
phenylpyridine with the corresponding styrene was
performed in D2O [Scheme 2, Eq. (2)]. This observa-
tion is explained by concurrent insertion of styrene
into the RuÀD species and subsequent b-hydride
elimination prior to carbon monoxide insertion and
reductive elimination.
Scheme 2. Ruthenium-catalyzed hydroaroylation through CÀH activation: Substrate
scope with different directing groups.[a,b] [a] Reactions were performed with styrene
(5 mmol), aryl bearing a directing group (0.5 mmol), and the ruthenium complex
(0.05 equiv.) under carbon monoxide pressure (3 MPa) at 1308C for 24 h. [b] Yields of
isolated products.
In conclusion, we developed a general protocol for
the ruthenium(II)-catalyzed carbonylative hydroaryla-
tion of alkenes through directed CÀH functionaliza-
tion. This three-component coupling process of 2-ar-
excess amount of the styrene derivative in some cases also led
to olefin dimerization, especially for styrenes substituted with
electron-withdrawing groups.
Next, we turned our attention to the variation of the hetero-
arene and the directing group (Scheme 2). Simple methyl- as
well as methoxy-substituted phenylpyridines gave the corre-
sponding ketones in good to excellent yields (Scheme 2, see
1h–5h). The best product yield was obtained if the arene ring
was substituted with a strong donating group (e.g., OMe, see
4h). Notably, phenyl derivatives bearing a pyrazole as directing
group were also effective in this coupling process without fur-
ther optimization, albeit with lower reactivity. Hence, 3,5-di-
methyl-1-phenyl-1H-pyrazole and 3-methyl-1-phenyl-1H-pyra-
zole were successfully converted into the corresponding prod-
ucts 7h and 8h, respectively (Scheme 2). Furthermore, thio-
phene-based heterocyclic compounds were examined; thereby,
2-(thiophen-3-yl)pyridine gave 8h in 74% yield. Notably, small
amounts (<10%) of the double hydroaroylation (C2 and C5
positions) product were observed in this case. Moreover, C3-di-
rected carbonylative hydroaroylation was successfully demon-
strated, and product 9h was isolated in an excellent 87%
yield.
Scheme 3. Ruthenium-catalyzed tandem hydroaroylation and selective
reduction.
In addition to heteroarenes, 2-styrylpyridine was shown to
undergo a novel tandem reaction involving hydroaroylation
and subsequent selective reduction of the C=C bond
(Scheme 3).[14] Product 10h was isolated in 42% yield. Remark-
ably, the recovered starting materials were not reduced under
these conditions.
Scheme 4. Experiments with different vinyl compounds (reactions performed
under standard conditions).
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Ed. 2011, 50, 6722; Angew. Chem. 2011, 123, 6854; e) X.-F. Wu, P. Anbar-
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Angew. Chem. 2012, 124, 5150; g) R. J. Lundgren, M. Stradiotto, Chem.
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[2] For selected recent general reviews and highlights on C-H activation
see: a) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew.
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Soc. Rev. 2011, 40, 1885.
Scheme 5. Deuteration experiments.
yl(heteroaryl)pyridines and related derivatives proceeds selec-
tively in water as the solvent with high atom efficiency.
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b) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879.
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Experimental Section
Synthesis of 3-phenyl-1-[2-(pyridin-2-yl)phenyl]propan-1-one:
Standard catalytic experiments were performed in a Parr Instru-
ments 4560 series 300 mL autoclave containing an alloy plate with
wells for six 4 mL Wheaton vials. [{(cod)RuCl2}n] (5 mol%) and
a magnetic stirring bar were placed in each of the vials, which
were then capped with a septum, equipped with an inlet needle,
and flushed with argon. Then, styrene (5 mmol), 2-phenylpyridine
(0.5 mmol), and H2O (1 mL) were added to each vial with a syringe.
The vials were placed in an alloy plate, which was then placed in
the autoclave. Once sealed, the autoclave was purged with CO sev-
eral times, then pressurized to 3 MPa at room temperature and
heated at 1308C for 24 h. Afterwards, it was cooled to room tem-
perature and vented to discharge the excess amount of CO. The
product was extracted with ethyl acetate (5ꢁ3 mL). The organic
layer was washed with brine, dried with Na2SO4, and evaporated to
yield the crude product. Purification by flash chromatography on
alumina gel (pH 9.5, heptane/EtOAc=80:20) gave the product
(64%) as a colorless oil.
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Acknowledgements
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chem.201302092.
We thank the State of Mecklenburg-Vorpommern and the Bun-
desministerium fꢀr Bildung und Forschung (BMBF) for financial
support. Also the research leading to these results received fund-
ing from the Innovative Medicines Initiative Joint Undertaking
(CHEM21) under grant agreement n8115360, resources of which
are composed of financial contribution from the European
Union’s Seventh Framework Programme (FP7/2007-2013) and
EFPIA companies’ in kind contribution. We also thank Dr. D. Mi-
chalik, Dr. W. Baumann, Dr. C. Fischer, and S. Buchholz (LIKAT)
for analytical support, as well as Sandra Leiminger (LIKAT) for
technical assistance.
[9] A. Tlili, J. Schranck, J. Pospech, H. Neumann, M. Beller, Angew. Chem. Int.
Ed. 2013, 52, 6293; Angew. Chem. 2013, 125, 6413.
[10] For recent reviews see: a) J. C. Leung, M. J. Krische, Chem. Sci. 2012, 3,
2202; b) M. C. Willis, Chem. Rev. 2010, 110, 725.
Keywords: carbonylation · CÀH activation · hydroaroylation ·
ruthenium · water
[11] For selected recent examples see: a) F. Xiao, Q. Shu, F. Zhao, O. Baslꢃ, G.
Deng, C.-J. Li, Org. Lett. 2011, 13, 1614; b) O. Baslꢃ, J. Bidange, Q. Shuai,
C.-J. Li, Adv. Synth. Catal. 2010, 352, 1145.
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Int. Ed. 2009, 48, 4114; Angew. Chem. 2009, 121, 4176; c) B. Gabriele, R.
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[14] For our recent work on using CO and water as reductant see: A. Tlili, J.
Schranck, H. Neumann, M. Beller, Chem. Eur. J. 2012, 18, 15935 and ref-
erences therein.
Received: February 11, 2014
[15] For recent mechanistic investigations on Ru-catalyzed CÀH activation
processes, see: a) I. Fabre, N. von Wolff, G. Le Duc, E. F. Flegeau, C. Bru-
Published online on && &&, 0000
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A. Tlili, J. Schranck, J. Pospech,
H. Neumann, M. Beller*
&& – &&
Ruthenium-Catalyzed Hydroaroylation
of Styrenes in Water through Directed
CÀH Bond Activation
Three-Component Hydroaroylation:
Hydroaroylation through CÀH activation
of (hetero)arenes bearing ortho-direct-
ing groups (DGs) proceeds in the pres-
ence of a ruthenium catalyst, carbon
monoxide, and styrenes. The shown
coupling process provides selective and
atom-economic access to (hetero)-
aromatic ketones.
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6
&
ÞÞ
These are not the final page numbers!