Regioselective ruthenium-catalyzed carbonylative direct arylation of five-membered and condensed heterocycles

Article abstract of DOI:10.1002/chem.201304314

A ruthenium-catalyzed carbonylative Ci￡H bond arylation process for the three-component synthesis of complex aryl-(hetero)aryl ketones in an aqueous solution has been developed. By exploiting the ortho-activating effect of nitrogen-containing directing groups, a regioselective, successive twofold C(sp²)i￡C(sp²) bond formation has been achieved. This straightforward catalytic process provides access to versatile products prevalent in multiple bioactive compounds and supplies a valuable functional group for subsequent transformations. Ci￡ H bond functionalization: A ruthenium-catalyzed carbonylative Ci￡H bond arylation process for the three-component synthesis of complex aryl-(hetero)aryl ketones in an aqueous solution has been developed (see scheme). By exploiting the ortho-activating effect of nitrogen-containing directing groups, a regioselective, successive twofold C(sp²) i￡C(sp²) bond formation has been achieved.

Full text of DOI:10.1002/chem.201304314

DOI: 10.1002/chem.201304314
Full Paper
&
Organic Chemistry
Regioselective Ruthenium-Catalyzed Carbonylative Direct
Arylation of Five-Membered and Condensed Heterocycles
Jola Pospech, Anis Tlili, Anke Spannenberg, Helfried Neumann, and Matthias Beller*[a]
Abstract: A ruthenium-catalyzed carbonylative CꢀH bond ar-
ylation process for the three-component synthesis of com-
plex aryl–(hetero)aryl ketones in an aqueous solution has
been developed. By exploiting the ortho-activating effect of
nitrogen-containing directing groups, a regioselective, suc-
cessive twofold C(sp2)ꢀC(sp2) bond formation has been ach-
ieved. This straightforward catalytic process provides access
to versatile products prevalent in multiple bioactive com-
pounds and supplies a valuable functional group for subse-
quent transformations.
Introduction
quire elaborate multistep syntheses. Indeed, common method-
ologies are based on the coupling between carbonyl com-
pounds with arylmetal species[6] or transition-metal-catalyzed
cross-coupling reactions of activated carboxylic acid derivatives
with organometallic compounds.[7] The direct arylation of ben-
zaldehydes or benzonitriles can be achieved upon the usage
of palladium-,[8] rhodium-[9] or nickel-based catalysts.[10] More-
over, an interesting organocatalytic approach exploiting the ac-
tivating effect of N-heterocyclic carbenes on heteroaryl-alde-
hydes has recently been reported by Gaunt and co-workers.[11]
Despite the existence of various methodologies for the forma-
tion of diaryl ketone linkages by carbonylative coupling, these
methods rely on the use of two pre-functionalized coupling
partners.[12,13] Therefore, the most direct and perhaps expedi-
ent route to these important pharmacophores and natural
products would be through the use of a direct carbonylative-
arylation of a CꢀH bond.
Di(hetero)aryl ketones constitute a common structural motif in
natural products and pharmaceuticals, and can be found in the
selective estrogen receptor modulator Raloxifene (Evista),[1] in
indole-based natural products uvarindole C,[2] calothrixin A and
B,[3] as well as marinopyrrole A and B (Figure 1).[4]
In recent years, numerous methodologies based on the CꢀH
bond functionalization have emerged for the construction of
C(sp2)ꢀC(sp2) bonds,[14] although, the corresponding carbonyla-
tive reactions have scarcely been investigated.[15,16] Within the
last decade, the utilization of ruthenium-catalysts for the for-
mation of CꢀC bonds has grown to encompass a large variety
of coupling partners and has subsequently found use in syn-
thesis.[17] Whereas multiple reports have focused on direct ary-
lation,[18,19] alkenylation,[20] and alkyne annulation,[21] carbonyla-
tive CꢀH bond functionalizations, on the other hand, are con-
fined to carbonylative hydroarylations of terminal alkenes.
Seminal examples for the addition of (hetero)aromatic CꢀH
bonds and CO to alkenes by chelation-assisted CꢀH bond func-
tionalization catalyzed by a Ru0-precursor have been devel-
oped by Moore,[22] Murai, Kakiuchi, and Chatani.[23] Recently,
our group has discovered that ruthenium(II) precatalyts display
a unique reactivity towards regioselective carbonylative aryla-
tions of arenes bearing an ortho-directing group (Scheme 1).[24]
Water, a benign and plentiful solvent, was found to be the
ideal medium for this catalytic reaction, offering excellent reac-
tivity and simple purification procedures.[25] In the interest of
Figure 1. Selected natural products bearing a heteroaryl–aryl methanone
moiety.
Moreover, bis(arylated) carbonyl compounds serve as valua-
ble progenitors for the assembly of complex molecules.[5] De-
spite this, these target compounds are difficult to access or re-
[a] J. Pospech, Dr. A. Tlili, Dr. A. Spannenberg, Dr. H. Neumann,
Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304314.
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Scheme 1. Ortho-directed ruthenium-catalyzed carbonylative direct arylation.
broadening the scope of this unique transformation, we inves-
tigated the applicability of this method to a variety of five-
membered and condensed heterocycles. This regioselective Cꢀ
H bond functionalization is biased by the pendent ortho-N-di-
recting group, yielding the corresponding diaryl methanone
derivatives in predictable and defined site-selectivity.[26] We
have demonstrated that carbonylative direct arylation can be
deliberately achieved at either the 2- or 3-position of the het-
erocycle by this method. The direct CꢀH bond functionaliza-
tion, presented here, provides a useful and convenient proto-
col for the activation of omnipresent CꢀH bonds. The straight-
forward access to versatile heteroaryl–aryl ketones, starting
from readily available or easily accessible starting materials and
an inexpensive catalyst system is shown and is showcased in
the synthesis of a Raloxifene analogue. Mechanistic experi-
ments have been performed and the key steps of the catalytic
cycle are discussed. The described methodology provides
a useful extension to existing CꢀH bond functionalization strat-
egies and should find broad utility in synthetic applications for
the synthesis of complex target molecules.[27]
Scheme 2. Comparison of the reactivity of 2-phenylpyridine (1a) and 3-(2’-
pyridyl)thiophene.
of the thiophene nucleophile 1b to the corresponding [3-(pyri-
din-2-yl)thiophen-2-yl](o-tolyl)methanone (3ba), which was iso-
lated in 87% yield; whereas the unreacted nucleophile 1a was
isolated quantitatively. Further optimization revealed that an
excess of the nucleophile was beneficial for the arylation of
heteroarenes and significantly accelerated the overall process,
resulting in higher yields of the desired coupling product
(Scheme 3, entry 1). Additional evaluation of different reaction
parameters (e.g., Ru-source, additives, base or solvent) did
not lead to any substantial improvements in yield or rate.[28]
Consequently, the scope for ruthenium-catalyzed carbonylative
direct arylation of heterocyclic nucleophiles and iodoarenes
was investigated under these optimized reaction conditions
(Scheme 2b).
Results and Discussion
Our initial efforts concerning the ruthenium-catalyzed carbony-
lative direct arylation were focused on the ortho-directed CꢀH
bond functionalization of 2-phenylpyridine (1a). Based on a de-
tailed study of the key reaction parameters, the best result was
achieved by using a practical catalytic system comprising of
[RuCl2(cod)]n (cod=1,5-cyclooctadiene), KOAc, and NaHCO3 as
the base. Operating in aqueous solution under carbon monox-
ide pressure (30 bar) created a uniquely active reaction envi-
ronment. In our previous protocol, a 1:2 ratio of the substrates
using the nucleophile 1 as the limiting reactant gave the best
results. However, the reaction proved to be rather sensitive
with respect to substitutions on the phenyl moiety. Gratifying-
ly, we found that pyridine-containing bis(heteroaryls), such as
3-(2’-pyridyl)thiophene (1b), were extremely effective in this
carbonylative coupling reaction (Scheme 2a). Encouraged by
this initial finding we strived to expand the substrate scope of
the reaction, with the goal of elucidating potential limiting fac-
tors of the direct carbonylative ortho-arylation. To this end,
a competition experiment between 2-phenylpyridine (1a) and
3-(2’-pyridyl)thiophene (1b) was conducted. Using an excess of
the competing nucleophiles revealed the selective conversion
Substrate scope for the C2-selective direct arylation
Under our optimized conditions, the ruthenium-catalyzed car-
bonylative direct arylation of 3-(2’-pyridyl)heteroarenes, includ-
ing thiophenyl, furanyl, and pyrrol-based heterocycles, was
conveniently accomplished by using a number of iodoarenes
in the presence of carbon monoxide. The pendent pyridine
moiety selectively biased the carbonylative coupling which al-
lowed for a highly regioselective functionalization at the 2-po-
sition of the investigated five-membered heterocycles. The cor-
responding heteroaryl–aryl ketones were isolated in moderate
to good yields (10–91%, Table 1).
The best result was obtained when 2b was reacted with 2-
iodotoluene (2a), resulting in a 91% of the desired [3-(pyridin-
2-yl)thiophen-2-yl](o-tolyl)methanone (3ba). In general, ortho-
substituted iodoarenes gave superior results relative to other
substitution patterns. Accordingly, 2-iodo-1,1’-biphenyl (2b),
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Table 1. C2-directed carbonylative arylation of five-membered heterocy-
cles.[a,b]
Table 2. Scope for the C3-directed carbonylative direct arylation of five-
membered and condensed heterocycles.[a,b]
[a] Reaction conditions: 3-(2’-pyridyl)heteroarene (1.0 mmol), iodoarene
(0.5 mmol), [RuCl2(cod)]n (5.0 mol%), KOAc (20 mol%), NaHCO3
(1.0 mmol), H2O (1.0 mL), CO (30 bar), 1208C, 20 h. [b] Isolated yields are
shown.
[a] Reaction conditions: 2-(2’-pyridyl)heteroarene (1.0 mmol), iodoarene
(0.5 mmol), [RuCl2(cod)]n (5.0 mol%), KOAc (20 mol%), NaHCO3
(1.0 mmol), H2O (1.0 mL), CO (30 bar), 1208C, 20 h. [b] Isolated yields are
shown. [c] K2CO3 was used as the base.
which possesses an increased steric demand furnished dike-
tones 3bb, 3cb, and 3 db in good yields of 72, 65, and 63%,
respectively. Surprisingly, the presence of further substituents
on the iodoarene coupling partner diminished the effective-
ness of this carbonylative coupling, for example, 4-iodo-m-
xylene (3d) gave merely 41% of isolated product, whereas uti-
lization of 2-iodomesitylene furnished only traces of the de-
sired product. However, polar and functionalized electrophiles,
including methoxy and fluorine substituents, were tolerated
and the corresponding products were obtained in fair yields
(56 and 55% for 3bf and 3bg, respectively). Noteworthy, the
unprotected amine functionality of 2-(1H-pyrrol-3-yl)pyridine
(3d) was effective in this reaction and competing acylation of
this substrate was not observed, which demonstrated the high
chemoselectivity of the catalytic system. These pyrrole-contain-
ing methanones 3da and 3 db were isolated in 47 and 63%
yields, respectively.
Substrate scope for the C3-selective direct arylation
The activation of the C3-position of five-membered heterocy-
cles is a challenging goal but can be enforced by the judicious
use of an ortho-directing group. The scope of the C3-directed
carbonylative direct arylation is depicted in Table 2. According-
ly, five-membered and condensed S- and O-containing hetero-
cycles 4 and 5 were successfully converted to the correspond-
ing aryl heteroaryl methanones 6aa–7 db in good yields (20–
71%, Table 2).
The isolated yields for 2-(2-heteroaryl)pyridines are compara-
ble to those that have been obtained for the C2-directed car-
bonylative coupling. However, the aforementioned beneficial
“ortho-effect” as seen regarding the iodoarene component was
not observed with this substitution pattern of the nucleophile.
Yields up to 68% were obtained (Table 2), whereas 2-furanyl-2’-
pyridine (4b) proved to be less efficient. Gratifyingly, when
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condensed heteroarenes, such as 2-(benzo[b]thiophen-2-yl)pyr-
idine (5a) and 2-(benzo[b]furan-2-yl)pyridine (5b) were em-
ployed, improved yields were achieved with diverse electro-
philes.
pling abilities compared to meta- and para-substituted electro-
philes. However, strongly chelating di-heteroarenes, such as 2-
(1H-pyrazol-1-yl)pyridine and 2-(1H-imidazol-1-yl)pyridine were
not suitable substrates in this reaction.
The cleavage of the pyrimidine-based directing element was
easily accomplished when starting with [1-(pyrimidin-2-yl)-1H-
pyrrol-2-yl](o-tolyl)methanone (10aa) and NaOEt in DMSO
at 1008C for 5 h,[31] yielding (1H-pyrrol-2-yl)(o-tolyl)methanone
(12) in 91% isolated yield (Scheme 3).
Substrate scope for the C2-selective direct arylation of N-
pyridyl and pyrimidyl heterocycles
The synthetic applicability of ortho-directed CꢀH bond func-
tionalization strategies is often constricted due to the presence
of the directing group. To address this constraint, the use of
a cleavable directing group can allow for a significant and ex-
pedient extension of this methodology. To demonstrate the
versatility of the direct carbonylation protocol, N-heteroarylat-
ed indole-based compounds, 9a and 9b, as well as 2-(1H-
pyrrol-1-yl)pyrimidine (8a) have been prepared according to
literature procedures.[29] These substrates demonstrated decent
reactivity and predictable site-selectivity of the carbonylative
coupling reaction under our optimized reaction conditions
(Table 3) and the resulting heteroaryl aryl ketones 10aa–11 bd
were isolated in moderate to good yields (45–75%). Again, 2-
substituted iodoarenes 2a and 2d possessed superior cou-
Scheme 3. Cleavage of the pyrimidine moiety.
To show the synthetic applicability of the presented reaction
we targeted the synthesis of an analogue of the estrogen re-
ceptor modulator Raloxifene.[1] Herein, the directing-group was
directly embedded in the core-structure of the pharmaco-
phore. The precursor 4’-methoxy-2-(6-methoxybenzo[b]thio-
phen-2-yl)pyridine (5c) was easily prepared by Suzuki–Miyaura
coupling of 6-methoxybenzo[b]thiophen-2-ylboronic acid and
2-bromo-5-methoxypyridine.
Table 3. Scope for the C2-selective carbonylative direct arylation of N-
arylated heterocycles.
Starting from the bismethoxylated substrate 5d and 4-fluo-
roiodobenzene (2g), the desired diarylketone 7dg was ob-
tained in 55% isolated yield utilizing our normal conditions
(Scheme 4). When 4’-methoxy-2-(6H-benzo[b]thiophen-2-yl)pyr-
idine (5c) was used as the core structure, the CꢀH bond car-
bonylation proceeded likewise in 53% yield.[30] The structure of
the corresponding product 7cg was confirmed by X-ray analy-
[a] Reaction conditions: 3-(2’-pyridyl)heteroarene (1.0 mmol), iodoarene
(0.5 mmol), [RuCl2(cod)]n (5.0 mol%), KOAc (20 mol%), NaHCO3
(1.0 mmol), H2O (1.0 mL), CO (30 bar), 1208C, 20 h. [b] Isolated yields are
shown. [c] K2CO3 as the base.
Scheme 4. Synthesis of pyridine-containing Raloxifene analogue 13: a) 1-(2-
hydroxyethyl)piperidine, NaH, DMF, 86%; b) BBr3, CH2Cl2, 79%.
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sis.[31] In analogy to previous Raloxifene syntheses, the next
step of the synthesis was the installation of the piperidine eth-
ylether by SNAr reaction onto the aryl CꢀF bond. Finally, depro-
tection of the two methoxy groups led to the target com-
pound 13 in 42% isolated yield from 5d. Distinct routes for
the syntheses of Raloxifene derivatives frequently involve Frie-
del–Crafts-type acylation of the benzo[b]thiophene followed
by Kumada–Corriu coupling for the CꢀC bond formation at the
2-position. Divergent from this strategy, our approach also
offers the opportunity for facile implementation of an isotopi-
cally labeled ketone functionality upon usage of labeled
carbon monoxide, which is a pre-requisite for the elucidation
of metabolic pathways of bioactive compounds.
subsequent to the oxidative addition proceeds fast compared
to the eventual reductive elimination that leads to the forma-
tion of the desired product.
Mechanistic studies
A brief mechanistic study concerning the key steps of the
ruthenium-catalyzed carbonylative direct arylation were con-
ducted. Initially the reversibility of the CꢀH bond cleavage by
using 3-(2’-pyridyl)thiophene (1b) was investigated. In this re-
spect, the reaction between 1b and 2-iodotoluene (2a) was
conducted in D2O under otherwise un-altered reaction condi-
tions (Scheme 5a). The process was stopped after 3 h and 65%
deuterium incorporation at the 2-position of 1b was deter-
1
mined by H NMR spectroscopy. After 20 h full consumption of
the electrophile was observed and the H/D-exchange at the 2-
position corresponded to 95% deuterium incorporation and
15% at C4. The H/D-exchange at the 4-position in product
3ba amounts to less than 7%. This observation clearly shows
that CꢀH bond cleavage follows a reversible mechanism.[32]
The sensitivity of the electronic nature of the electrophile on
the rate of the oxidative addition was explored by an intermo-
lecular competition experiment between electron-rich 4-me-
thoxyiodobenzene (2 f) and electron-poor 4-fluoroiodobenzene
(Scheme 5b). The substrates were employed in a 1:2:2 ratio
that corresponds to an eightfold excess of electrophile relative
to the optimized reaction conditions (with nucleophile 1b as
the limiting reactant). Quenching of the reaction after 4 h pro-
vided a product distribution of 3bf and 3bg in a 1.2:1.0 ratio
according to 1H NMR spectroscopy. Consequently, the oxidative
addition should not represent the rate-determining step in the
catalytic cycle. In some cases, most dominant in the C2-direct-
ed carbonylative arylation of five-membered heterocycles
(Table 1), higher yields were obtained using ortho-substituted
electrophiles. Attempting to determine the influence of the
substitution pattern of the electrophile, an intermolecular com-
petition experiment between ortho- and para-substituted elec-
trophiles, 2a and 2l, was conducted (Scheme 5c). However, it
was not evident that ortho-substituted 2a possess a superior
reactivity compared to para-substituted 2l. The corresponding
products 3ba and 3bl, respectively, were formed in a constant
54:46 (Scheme 6).
Scheme 5. a) Investigation of H/D exchange at C2 of 1b. b) Intermolecular
competition experiment between electron-rich and -poor electrophiles 3bf
and 3bg. c) Intermolecular competition experiment between ortho- and
para-substituted electrophiles. *=formally footnote a.
Moreover, the reaction between 4-(pyridin-2-yl)phenol (1e)
with 2-iodotoluene (2a) showed the occurrence of two side-
products 14 and 15, resulting from a competing background
reaction leading to CꢀO bond formation. Consequently, we
reasoned that the CO-insertion in the ruthenium–aryl bond
Scheme 6. Competitive attack of C- and O-nucleophiles.
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Experimental Section
General procedure for the carbonylative direct arylation
Six glass vials (4 mL) were charged with [RuCl2(cod)] polymer
(7.0 mg, 5.0 mmol%), NaHCO3 (84 mg, 1.0 mmol, 2.0 equiv), and
KOAc (9.8 mg, 20 mol%) and a stirring bar. All vials were placed
into an alloy plate, equipped with a septum and an inlet needle,
evacuated and backfilled with argon before 2-(thiophen-3-yl)pyri-
dine (161 mg, 1.0 mmol, 2.0 equiv), 2-iodotoluene (112 mg,
0.51 mmol, 1.0 equiv), and degassed H2O (1.0 mL) were added. The
alloy plate with six vials was then placed in an autoclave (300 mL,
Parr Instruments 4560 series). At room temperature, the autoclave
was flushed with CO (3ꢁ5 bar) and finally pressurized with CO
(30 bar). The autoclave was heated to 1208C for 20 h, cooled to
room temperature, and the remaining CO was released slowly. The
apparatus was flushed with nitrogen with vigorous stirring. The re-
action mixture was further diluted with EtOAc (5 mL) and H2O
(5 mL). The phases were separated and the aqueous layer was ex-
tracted with EtOAc (3ꢁ3 mL). The combined organic layer were
washed with brine (10 mL) and dried over Na2SO4. The solvent was
removed under reduced pressure and the crude product was puri-
fied by flash-chromatography (n-heptane/EtOAc=8:1!4:1). The
title compound (129 mg, 0.46 mmol, 91%) was obtained as a trans-
lucent solid.
Scheme 7. Proposed catalytic cycle for the ortho-directed carbonylative
direct arylation.
Acknowledgements
The catalytic cycle depicted above summarizes the key-steps
of the ruthenium-catalyzed carbonylative coupling. Based on
our experimental results we propose a catalytic cycle begin-
ning with the initial ortho-metalation starting from a RuII spe-
cies (A!B, Scheme 7), followed by a reversible acetatate-as-
sisted hydrogen abstraction (B!C). Following this, the chelat-
ed ruthenium species C undergoes oxidative addition upon
formation of complex D that readily reacts with carbon mon-
oxide upon formation of Ru–acyl complex E (C!D!E). Even-
tually, the second C(sp2)ꢀC(sp2) bond formation proceeds by
reductive elimination upon formation of the desired product
and regeneration of the active RuII-catalyst (E!A). Currently,
we propose that the final reductive elimination is the rate-de-
termining step for the overall catalytic cycle.[33]
We thank the state of Mecklenburg-Vorpommern and the Bun-
desministerium fꢂr Bildung und Forschung (BMBF) for financial
support. The support of the analytic division of the institute
and by Dr. D. Michalik (Rostock University) is gratefully ac-
knowledged. Dr. I. Fleischer, Dr. S. Fenner , and B.T. Worrell are
especially thanked for their constant interest and fruitful dis-
cussions. Dr. I. Fleischer and Dr. S. Fenner (University of Cam-
bridge) are especially thanked for their constant interest and
helpful discussions. B. Worrell is thanked for proofreading the
manuscript.
Keywords: carbonylative
functionalization · heterocycles · multicomponent reactions ·
coupling
·
CꢀH
bond
ruthenium
Conclusion
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[33] Although, up to now, endeavors attempting to accelerate this step
(e.g., addition of weakly coordinating counteranions) did not lead to
fundamental improvements.
Received: November 4, 2013
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Published online on February 12, 2014
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