Rhodium-Catalyzed Annelation of Benzoic Acids with α,β-Unsaturated Ketones with Cleavage of C?H, CO?OH, and C?C Bonds

Article abstract of DOI:10.1002/anie.201901309

In the presence of a [Cp*RhCl₂]₂ catalyst, the Lewis acid In(OTf)₃, and the mild base Na₂CO₃, aromatic carboxylates and α,β-unsaturated ketones undergo a unique hydroarylation/Claisen/retro-Claisen pr

Full text of DOI:10.1002/anie.201901309

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Accepted Article
Title: Rh-Catalyzed Annelation of Benzoic Acids with α,β-Unsaturated
Ketones with Cleavage of C–H, CO–OH, and C–C Bonds
Authors: Lukas J Goossen, Guodong Zhang, Zhiyong Hu, Florian
Belitz, Yang Ou, and Nico Pirkl
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901309
Angew. Chem. 10.1002/ange.201901309
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10.1002/anie.201901309
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Rh-Catalyzed Annelation of Benzoic Acids with α,β-Unsaturated
Ketones with Cleavage of C–H, CO–OH, and C–C Bonds
Guodong Zhang, Zhiyong Hu, Florian Belitz, Yang Ou, Nico Pirkl and Lukas J. Gooßen*
Abstract: In the presence of a [Cp*RhCl2]2 catalyst, the Lewis acid
In(OTf)3 and the mild base Na2CO3, aromatic carboxylates and -
unsaturated ketones undergo a unique hydroarylation/Claisen/retro-
Claisen process to give the corresponding indanones. In this
carboxylate-directed ortho-C–H annelation, the C–COR bond of the
ketone and the CO–OH group of the aromatic carboxylate are cleaved,
and the hydroxy group is transferred from the aromatic to the aliphatic
acyl residue. This reactivity is synthetically useful particularly when
starting from cyclic ketones, which are converted into indanones
bearing aliphatic carboxylate side-chains, thus greatly increasing the
molecular complexity of aromatic carboxylates in a single step.
of carboxylate-directed sp2 C−H ortho-functionalizations have
been developed e.g. by Yu,[8] Li,[9] Daugulis,[10] Larrosa,[11]
Ackermann,[12] Su,[13] Baidya,[14] our group,[15] and others.[16]
The predominant pathways for ortho-C–H functionalizations
of carboxylates with -unsaturated carbonyl compounds are
oxidative Heck-type couplings (Scheme 1a), which lead either to
ortho-vinylated carboxylates, or to alkyl or alkenyl lactones.[17] For
some heteroarenes, e.g. thiophenes or furans, this reaction
proceeds with concomitant decarboxylation.[18] Hydroarylation
pathways give rise to ortho-alkylated benzoates (Scheme
1b).[15a,16a] For maleimides, a decarboxylative variant is also
known.[14c,19] Still, we believed that many exciting synthetic
opportunities would open up, if the carboxylate group could be
funneled into new reaction pathways after the hydroarylation step.
We, thus, investigated the reaction of methyl vinyl ketone with o-
toluic acid in the presence of various Ru and Rh catalysts aiming
at the discovery of a reaction, in which the carboxylate acts as a
deciduous directing group.[15a,b] However, to our surprise, we
detected 7-methyl-1-indanone and acetic acid rather than the
targeted methyl o-tolylethyl ketone, when using [Cp*RhCl2]2 as
the catalyst (Scheme 1c).
Over the past two decades, transition metal-catalyzed directed C–
H functionalizations have undergone tremendous development,
evolving from pioneering examples into robust and versatile tools
for modern organic synthesis.[1] Initially, this approach was often
limited by the use of complex directing groups[2] which needed to
be installed and later removed, thus adding steps to the overall
process. In state-of-the-art methods, the selectivity can be
enforced even by ubiquitous functionalities, including ketones,[3]
hydroxy,[4] or carboxylate groups.[5]
This was an exciting finding, not only because 1-indanones
are a privileged substructure in various bioactive molecules,[20] but
also because this product could have formed only with cleavage
of a CO–OH group under basic conditions. Such reactivity is
highly desirable but rare. In sharp contrast to its derivatives, free
carboxylic acids do not easily undergo nucleophilic addition/
elimination reactions.[21] Whereas esters react with enolates to
form -keto ester enolates and alcohols, carboxylic acids would
be deprotonated by such nucleophiles, disrupting the C–C bond-
forming process.[22] However, our mechanistic analysis of the
above experimental findings seemed to imply that C–C bond
formation via a Claisen-type condensation starting directly from
the free carboxylic acid must have been involved (Scheme 2). It
suggests that such reactions are possible without prior prep-
aration of esters and consumption of stoichiometric strong base.
a) oxidative olefination/lactonization: Miura, Ackermann, Li et al.
Pd, Rh, or Ru
or
[O]
b) hydroarylation: Gooßen, Baidya, Ackermann et al.
Rh, or Ru
c) this work: C-H, CO-OH, and C-C bond cleavage
[Rh]
Based on the well-documented ability of [Cp*RhCl2]2 to
promote ortho-C–H functionalizations,[23] it is safe to assume that
the reaction is initiated by base-assisted, concerted metalation-
deprotonation (CMD). There is also ample literature evidence that
unsaturated compounds insert into aryl–rhodium bonds, pointing
Scheme 1. Carboxylate-directed C−H coupling with α,β-unsaturated carbonyls.
The key advantages of carboxylate directing groups are their
broad availability and the fact that they can be removed
tracelessly or used as anchor points for further regiospecific C–C
or C–heteroatom bond-forming reactions via decarboxylative
coupling.[6] Inspired by pioneering work by Miura,[7] a huge variety
towards III as
a A
subsequent catalytic intermediate.[24]
conceivable route to the indanone product involves the
intramolecular substitution of the hydroxy group by the rhodium
enolate, followed by reductive elimination of an acyl indanone.
Such compounds are known to undergo retro-Claisen
deacylations in the presence of various Lewis acids.[25] This step
must occur rapidly, because if the diketone V accumulates, it will
undergo Michael additions leading to unwanted aggregates. In
the overall process, the hydroxy group is transferred from an
aromatic to an aliphatic acyl group, which can be expected to
G. Zhang, Z. Hu, F. Belitz, Y. Ou, Prof. Dr. L. J. Gooßen
Fakultät für Chemie und Biochemie
Ruhr-Universität Bochum
Universitätsstr. 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201901309
Angewandte Chemie International Edition
COMMUNICATION
have only minimal influence on the thermodynamics of the
reaction.
acid (1t), the product 3ta' forms. Since the carbonyl group of
indanones is ineffective as DG in Rh-catalyzed C–H activation,[3a]
the second hydroarlyation must have taken place while the
carboxylate group was still intact. Hence, the Rh enolate
formation must be reversible (see Scheme 2, III, IV), and the
Claisen condensation slower than the hydroarylation step. After
double hydroarylation of 1t, only one of the two ketone side chains
can undergo the follow-up Claisen steps leading to 3ta'.
+ base
[Rh]
1
H2O, base H+
Claisen
V
CMD
Table 1. Coupling of arenecarboxylic acids with 2-cyclohexen-1-one.[a]
retro-Claisen
[RhCp*Cl2]2
IV
III
Na2CO3, In(OTf)3
I
Toluene/H2O
1
2a
3
base
base H+
olefin insertion
3
2
II
R = Me,
R = Et,
R = NHPh, 3ca 70%
R = OMe, 3da 58%
R = NHAc, 3ea 50%
3aa 72% (56%)[b]
3ba 60%
R = Me,
R = Ph,
R = CF3,
3ga 56%
3ha 54%
3ia 53%[c]
R = Ac,
R = CO2Me, 3ka 52%[c]
3ja 50%[c]
Scheme 2. Mechanistic blueprint.
R = Cl,
3fa 40%
This reaction pathway could open up an interesting access to
indanone moieties that would compare favorably with established
syntheses, e.g. via Friedel-Crafts cyclization of cinnamic acid or
cinnamoyl chloride derivatives,[26] or via hydroacylation of
unsaturated benzaldehyde derivatives.[27] In the case of cyclic
alkenone starting materials, the acyl leaving group would remain
tethered to the indanone ring, thus further increasing product
complexity.
R = Br, 3qa 51%
R = CF3, 3ra 49%
R = Me,
R = OMe, 3ma 50%
R = F,
R = Cl,
R = Br,
3la 70%
3na 65%
3oa 58%
3pa 64%
3sa, 71%
Motivated by these synthetic opportunities, we performed a
holistic optimization of the catalyst system and the reaction
conditions using the model reaction of 2-methylbenzoic acid (1a)
and 2-cyclohexen-1-one (2a) in order to turn this idea into an
effective chemical process (Table S1). Among all catalysts tested,
[Cp*RhCl2]2 gave the best yield of 3a. A Lewis acid was required
to promote the desired reaction. The best results were obtained
with In(OTf)3. A protic solvent was found to be essential. 79% yield
was achieved at 120 °C using a slight excess of 2a, 5 mol%
[Cp*RhCl2]2, and 15 mol% In(OTf)3 in a biphasic toluene/water
mixture buffered with 0.6 equivalents of Na2CO3. The identity of
the indanone product was unambiguously determined by single
crystal X-ray diffraction (Supporting information).
3ta, 31%
3ta´, 10%
[a] Reaction conditions: 0.5 mmol of 1a-t, 0.6 mmol of 2a, 5 mol% of
[Cp*RhCl2]2, 15 mol% of In(OTf)3, 0.6 equiv. of Na2CO3, 0.15 mL of
toluene/H2O (3:2), 120 °C, 16 h, argon; isolated yields. [b] 10 mmol scale.
[c] 0.75 mmol of 2a, 6 mol% of [Cp*RhCl2]2, 0.12 mL of toluene/H2O (3:1).
We next investigated the scope with regard to -unsaturated
ketones in the coupling of 2-methylbenzoic acid (1a) (Table 2).
Non-cyclic methyl alkenyl ketones yielded the corresponding
indanones in moderate yields along with sodium acetate as the
byproduct (3ab-3af). If one considers how easily and sustainably
these substrates are accessible from acetone, this may well be
one of the most attractive synthetic entries to substituted
indanones.
The substrate scope was investigated using the coupling of
various arenecarboxylic acids with 2-cyclohexen-1-one (2a)
(Table 1). Electron-poor and electron-rich benzoic acids reacted
equally well, and wide variety of functional groups are tolerated,
including keto-, ester, bromo, amide, and even N–H groups. For
meta-substituted benzoic acids, the reaction proceeded with high
regioselectivity in favor of the less hindered ortho-position.
Benzoic acids bearing strongly electron-withdrawing groups gave
only moderate yields even at an increased catalyst loading. The
tolerance of acetamido, methoxycarbonyl, and acetyl groups
opens up opportunities for follow-up directed C–H
functionalizations.[2a,b] When starting with unsubstituted benzoic
We placed special emphasis on cyclic enone substrates,
since these give uniquely efficient access to indanones bearing
aliphatic carboxylate side chains. The carboxylate group can then
be utilized as a leaving group in various decarboxylative couplings
including
Hunsdiecker-Borodin
reactions,
photochemical
couplings, decarboxylative elimination, and many others.[28] 2-
Cyclohexen-1-ones bearing alkyl or aryl side chains in various
positions were successfully converted into the alkylcarboxlate-
functionalized indanones, demonstrating the robustness of this
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10.1002/anie.201901309
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reaction variant (3ah-3aq). 2-Cyclopenten-1-one also reacted
well (3ag), whereas smaller rings did not give satisfactory yields.
that the cooperative action of [Cp*RhCl2]2 and In(OTf)3 is required
to facilitate this regioselective annelation of benzoic acids via C–
H activation and cleavage of C–C and CO–OH bonds
Table 2. Coupling of 2-methylbenzoic acid with α,β-unsaturated ketones.[a]
a)
[RhCp*Cl2]2
[RhCp*Cl2]2
Na2CO3, In(OTf)3
( )n
Na2CO3, In(OTf)3
75% D
Toluene/H2O
( )n
Toluene/D2O, 120°C
1a
2
3
1a
(D)-1a
R = H,
R = Me,
3ab 31%
3ac 56%
b)
[RhCp*Cl2]2
R = i-C3H7, 3ad 60%[b]
R = n-C3H7, 3ae 64%
R = n-C5H11, 3af 62%
Na2CO3, In(OTf)3
Toluene/H2O, 120°C
(
13C)-1t
2a
(
13C)-3ta
3ag 55%
c)
Na2CO3, In(OTf)3
1a
Toluene/H2O, 120 °C
4aa
3aa 80%
R = Me,
R = CH2Ph, 3ai 48%[b]
3ah 52%[c]
R = Me,
3aj 50%[c]
R = n-C5H11, 3ak 55%[b]
[RhCp*Cl2]2
Na2CO3
R = Me,
R = n-C3H7,
3al 53%
3am 51%
3an 57%[b]
d) 1a
2a
3aa
R = n-C7H15
,
Toluene/H2O
120°C, 1.5 h
R = Ph,
3ao 56%
R = CH2CO2Me, 3ap 52%
R = CH2COMe, 3aq 58%[b]
4aa
trace
5aa
3ar 50%[d]
N.D.
18%
e)
[a] Reaction conditions: 0.5 mmol of 1a, 0.6 mmol of 2b-r, 5 mol% of
[Cp*RhCl2]2, 15 mol% of In(OTf)3, 0.6 equiv. of Na2CO3, 0.15 mL of
toluene/H2O (3:2), 120 °C, 16 h, argon; isolated yields. [b] 0.75 mmol of 2, 6
mol% of [Cp*RhCl2]2, 0.12 mL of toluene/H2O (3:1), 140 °C. [c] 140 °C. [d]
1.0 mmol of 2, 150 °C.
[RhCp*Cl2]2, Na2CO3
In(OH)3, TfOH
Toluene/H2O, 120°C
1a
2a
3aa 6%
The reaction was successfully scaled up to 10 mmol for
product 3aa as an example (Table 1). If the reaction is stopped
after 1.5 h, the diketone 4aa can be isolated in good selectivity,
opening up further synthetic opportunities (Scheme 3).
Scheme 4. Mechanistic investigations.
In conclusion, the reaction of aromatic carboxylic acids with
-unsaturated ketones in the presence of a bimetallic Rh/In
catalyst system opens up a versatile synthetic entry to the
important substance class of indanones. It also demonstrates that
the long-standing challenge of substituting the hydroxy groups in
carboxylic acids with carbon nucleophiles can be achieved within
the coordination sphere of rhodium. If this reaction mode can be
extended to intermolecular Claisen couplings of carboxylic acids
with enolizable carbonyl compounds, it might open up many
opportunities for sustainable C–C bond-forming reactions that
work without either prior esterification or strong bases.
[RhCp*Cl2]2
Na2CO3, In(OTf)3
Toluene/H2O
120°C, 1.5 h
1a
2a
4aa 57%
Scheme 3. Preferential formation of diketones at incomplete conversion.
Several control experiments were conducted to shed some
light on the reaction mechanism. When heating o-tolyl carboxylate
t
in the presence of [Cp*RhCl2]2 in AmylOH/D2O, selective ortho-
deuteration was observed, indicating reversible C−H bond
cleavage (Scheme 4a). A 13C-labeling experiment confirmed that
the carbonyl group of the indanone originates from the benzoate
(Scheme 4b). Upon treatment with In(OTf)3, the bicyclic diketone
4aa, which is the main product at incomplete conversion of 1a, is
smoothly converted into 3aa, supporting the proposed reaction
pathway via Claisen and retro-Claisen condensation steps
(Scheme 4c). In the absence of a Lewis acid, the Claisen
condensation is sluggish, and deacylation is even slower, so that
intermediate 4aa directly enters Michael addition pathways
leading to complex product mixtures (Scheme 4d). The hydrolysis
products of In(OTf)3, namely InOx(OH)y and TfOH are inactive
(Scheme 4e), demonstrating that the reaction takes place faster
than the hydrolysis of the Lewis acid. All these findings confirm
Experimental Section
An oven-dried 10 mL vessel was charged with [Cp*RhCl2]2 (16.3 mg,
0.025 mmol), Na2CO3 (32 mg, 0.30 mmol), In(OTf)3 (57.9 mg, 0.075 mmol),
and the corresponding benzoic acid (0.50 mmol). Under an argon
atmosphere, toluene (90 µL), H2O (60 µL), and the corresponding cyclic
-unsaturated ketone (0.60 mmol) were added via syringe. The resulting
mixture was stirred at 120 °C for 16 h, then acidified with 0.1 M HCl (pH =
2-3) and extracted with ethyl acetate (5 × 20 mL). The combined organic
layers were dried over MgSO4, filtered, and the volatiles were removed
under reduced pressure. The residue was purified by column
chromatography (SiO2, 2.5% formic acid and 2.5% methanol in ethyl
acetate/cyclohexane) yielding the corresponding alkylcarboxylic acid.
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10.1002/anie.201901309
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COMMUNICATION
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Acknowledgements
Funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) under Germany’s Excellence
Strategy – EXC-2033 – Projektnummer 390677874 and SFB‐
TRR 88 “3MET”. We thank UMICORE for donating chemicals,
BMBF and the state of NRW (Center of Solvation Science
“ZEMOS”), and the CSC (fellowships to G.Z., Z.H., and Y.O.) for
financial support, and Dr. A. Del Grosso for X-ray measurement,
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Keywords: rhodium • C−H activation • aromatic carboxylates •
aliphatic carboxylates • annelation
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10.1002/anie.201901309
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COMMUNICATION
Guodong Zhang, Zhiyong Hu, Florian
Belitz, Yang Ou, Nico Pirkl and Lukas J.
Gooßen*
Rh
In
Toluene/ H2O
Page No. – Page No.
broad scope
waste-free
ideal switch
Rh-Catalyzed Annelation of Benzoic
Acids with α,β-Unsaturated Ketones
with Cleavage of C–H, CO–OH, and
C–C Bonds
In the presence of a bimetallic Rh/In catalyst, aromatic carboxylic acids react with
α,β-unsaturated ketones with formation of two new C-C bonds along with the
selective cleavage of non-activated C–H, CO–OH and C–COR bonds. The resulting
annelation opens up a versatile synthetic entry to functionalized indanones.
This article is protected by copyright. All rights reserved.