Iridium-Catalyzed Synthesis of Substituted Indanones from Aromatic Carboxylates and Unsaturated Ketones

Article abstract of DOI:10.1021/acscatal.9b02536

A catalytic annulation is presented that provides straightforward, modular synthetic access to 3-substituted indanones from benzoic acids and α,β-unsaturated ketones. It is catalyzed by a bimetallic Ir/In system and proceeds via hydroarylation followed by

Full text of DOI:10.1021/acscatal.9b02536

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Letter
Iridium-Catalyzed Synthesis of Substituted Indanones
from Aromatic Carboxylates and Unsaturated Ketones
Guodong Zhang, Zhiyong Hu, Giulia Bertoli, and Lukas J. Gooßen
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02536 • Publication Date (Web): 02 Aug 2019
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ACS Catalysis
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Iridium-Catalyzed Synthesis of Substituted Indanones from Aro-
matic Carboxylates and Unsaturated Ketones
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Guodong Zhang, Zhiyong Hu, Giulia Bertoli, and Lukas J. Gooßen*
Fakultät für Chemie und Biochemie; Ruhr-Universität Bochum; Universitätsstr. 150, 44801 Bochum (Germany)
ABSTRACT: A catalytic annulation is presented that provides straightforward, modular synthetic access to 3-substituted
indanones from benzoic acids and α,β-unsaturated ketones. It is catalyzed by a bimetallic Ir/In system and proceeds via
hydroarylation followed by Claisen condensation and optional retro-Claisen deacylation. The annulation may be combined
into a one-pot procedure with the synthesis of the unsaturated ketone substrates from aldehydes and acetone. Two com-
plementary reaction protocols are provided that are applicable to diversely functionalized electron-rich and electron-poor
substrates.
KEYWORDS: iridium; C−H activation; benzoic acids; substituted indanones; diketo compounds
Substituted indanones have distinct biological activity,1
and are thus common substructures in pharmaceuticals.2
Moreover, they are valuable synthetic intermediates.3 Tra-
ditional synthetic entries to substituted indanones, such as
inter- or intramolecular Friedel-Crafts reactions of cin-
namic acid derivatives,4 suffer from rather harsh, acidic
conditions and/or low regioselectivities.
catalyzed C–H coupling of acylsilanes with TMS-
arylacetylenes (d).9 The CsF-promoted reductive cross-
coupling of 1,3-indanedione monotosylhydrazone with an
arylboronic acid exemplifies a synthetic strategy in which
an organic residue is introduced selectively in the 3-posi-
tion of a pre-formed indanone ring (e).10
As an advantageous alternative to these methods, we
herein disclose a modular iridium-catalysed synthesis of
indanones from widely available benzoic acid, aldehyde,
and methyl ketone building blocks.11
Scheme 1. Strategies for the synthesis of 3-substituted
indanones.
Previous syntheses of 3-substituted indanones
Scheme 2. Mechanistic blueprint of the targeted an-
nelation.
(b) Rh or Co
(a)
(c)
base
[M]
Pd or Rh X = I, Br, OTf, ONf, Bpin
Pd/CO
1
H2O, base H+
Claisen
CMD
(e)
(d)
3
H2O
Au
CsF
ArB(OH)2
retro-
Claisen
R = alkyl or Ar
I
This work
IV
III
R2CO2H
4
Ir
base
R2CO2H
2
base H+
olefin insertion
catalytic annulation
optional deacylation
R1CHO
II
Transition metal-catalyzed reactions aiming at the regiose-
lective construction of substituted indanones (Scheme 1),5
including Pd-catalyzed carbonylative cyclisations of iodo-
substituted 1,1-diaryl alkenes (a)6 and Rh- or Co-catalyzed
hydroacylations (b) have opened up regioselective entries
to this substrate class,7 but depend on the availability of
elaborate substrates. The same limitation applies to the re-
ductive cyclisation of 2-substitued chalcones (c)8 and Au-
In continuation of research performed in the groups of
Yu,12 Li,13 Daugulis,14 Larrosa,15 Ackermann,16 Su,17 our
group,18 and others19 on carboxylic acids as directing groups
in C–H functionalizations, we recently discovered a new
reaction mode of benzoic acids with α,β-unsaturated ke-
tones (Scheme 2).20 In the presence of a Rh catalyst, the
benzoic acid 1 undergoes ortho-metalation to intermediate
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ACS Catalysis
I,21 which in turn carbometalates the α,β-unsaturated ke-
Page 2 of 7
4aa was observed in the presence of the Rh/In system (en-
try 1). In order to slow down deacylation, the Lewis acid
InOTf was left out, and the reaction mixture was buffered
with aqueous K2CO3. Under these conditions, neither ru-
thenium nor rhodium systems gave satisfactory conversion
(entries 2-3).
1
2
3
4
5
6
7
8
tone 2 to give III. Rather than continuing along known
Heck-type or decarboxylative hydroarylation pathways,22
the Rh enolate then substitutes the unprotected carbox-
ylate OH group to give the Claisen product 3. Under Lewis-
acidic reaction conditions, this step is inevitably followed
by a retro-Claisen deacylation,23 furnishing the indanone 4.
The new reaction concept promised to open up a window
of opportunities for the synthesis of indanones, but unfor-
tunately, the scope of the prototypical Rh/In catalyst was
rather limited. Best results were obtained with cyclic ke-
tone substrates, whereas the yields were only moderate for
simple alkenyl methyl ketones, and all test reactions had
failed for 3-aryl alkenones. Moreover, it was not possible to
stop the reaction at the acyl intermediate III. With Ru,
similar substrates were reported to enter complex reaction
cascades with double incorporation of the enone substrate
into 2-substituted indanones and spirocyclic derivatives.24
In an extensive screening of various catalyst metals, solely
[IrCp*Cl2]2 gave significant amounts of the desired product
3aa, along with the deacylation product 4aa (entry 4-5).25
Further investigations revealed that the base has a decisive
influence on the ratio between these products (entries 6-
9). Only with KOAc or NaOAc, 3aa was obtained selec-
tively, all other bases tested led to deacylation. After fur-
ther adjustments (entries 10-11), the highest yield of 3aa
was obtained with 3 mol% [IrCp*Cl2]2 as the catalyst in the
presence of 2.5 M aqueous KOAc (1.0 equiv.) and 1.6 equiv.
of the alkenone at 150 °C without solvent (Protocol A).
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In the presence of K2CO3, the deacylated indanone 4aa was
formed in significant amounts (entry 5). Its fraction in-
creased in aqueous polar organic solvents, particularly in
tAmylOH/H2O, where it was the major product (entries 12-
14). Adding catalytic amounts of Lewis acids further pro-
moted the deacylation step, and best results were obtained
with In(OTf)3 (entries 15−18).23f The highest selectivity for
4aa was obtained when stirring 1a with 1.6 equiv. of the
alkenone in the presence of 3 mol% [IrCp*Cl2]2 and 7.5%
In(OTf)3 with 0.4 equiv. of a 1 M solution of K2CO3 in a 3:1
tAmylOH/water mixture at 140 °C (Protocol B).
Table 1. Optimization of the reaction conditionsa
catalyst
base, additive
solvent, Ar
1a
2a
3aa
4aa
3aa
(%)
4aa
(%)
catalyst
base, additive
solvent
1
[RhCp*Cl2]2 K2CO3, In(OTf)3 tAmOH
N.D 35
20
2
3
[RhCp*Cl2]2 K2CO3
[Ru(cy)Cl2]2 K2CO3
[IrCODCl]2 K2CO3
-
2
-
N.D N.D
N.D N.D
Table 2. Substrate scope of 2-acyl-3-arylindanonesa
4
5
7
8
6
9
10
-
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
K2CO3
-
39
35
37
49
55
63
72
28
25
8
[IrCp*Cl2]2, KOAc
H2O
K3PO4
-
1
2
3
Na2CO3
NaOAc
KOAc
KOAcb
KOAcb
K2CO3
-
21
-
N.D
N.D
3
-
-
3aa 68%
3ca 58%
3la 51%
3ag 53%
3at 76%
3ma 52%
11c [IrCp*Cl2]2
-
3
12
13
14
15
16
17
18
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
dioxane
NMP
tAmOH
tAmOH
20
K2CO3
N.D 21
K2CO3
24
44
3na 57%
3ai 48%
3av 46%
3ac 53%
3ah 51%
K2CO3,Fe(OTf)3
N.D 60
N.D 71
N.D 80
N.D 84
K2CO3, Zn(OTf)2 tAmOH
K2CO3, Sc(OTf)3 tAmOH
K2CO3, In(OTf)3 tAmOH
3as 70%
3au 60%
aConditions: 0.5 mmol of 1a, 0.8 mmol of 2a, 3 mol% of cata-
lyst, 7.5 mol% of additive, 0.4 equiv. of base, 0.2 mL of H2O
or of 3/1 solvent/H2O, 140 °C, 16 h. Yields determined by H
1
NMR using 1,3,5-trimethoxybenzene as the internal standard.
b1.0 equiv. c150 °C. tAmOH = tert-amyl alcohol, cy = p-cymene.
3aw 41%
aConditions: 0.5 mmol of 1, 0.8 mmol of 2, 3 mol% of
[IrCp*Cl2]2, 0.5 mmol of KOAc, 0.2 mL H2O, 150 °C, 16 h.
We started our search for an effective and tuneable catalyst
using the reaction of 2-methylbenzoic acid (1a) and β-phe-
nyl vinyl ketone (2a) as a model (Table 1). As expected, un-
satisfactory conversion mostly to the deacylated product
Having thus found two complementary protocols for the
non-deacylative (A) and deacylative annulation of benzoic
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ACS Catalysis
acids (B), we next investigated their preparative applicabil-
ity to the synthesis of indanones. The scope of the non-
deacylative protocol (A) was investigated by coupling rep-
resentative aromatic carboxylic acids with several unsatu-
rated ketones. As shown in Table 2, aliphatic as well as ar-
omatic substituents bearing electron-donating or electron-
withdrawing groups are smoothly converted (3aa-3at).
Both aliphatic and aromatic acyl groups can be introduced
in the 2-position (3au-3aw).
with regard to the aromatic carboxylic acid was tested us-
ing β-phenyl vinyl ketone (2a) as the coupling partner (Ta-
ble 3). Benzoic acids bearing electron-donating or elec-
tron-withdrawing groups were smoothly coupled to give
moderate to good product yields. For meta-substituted
benzoic acids, C–H activation occurred selectively at the
less hindered ortho-position (4ga-4ja). Multisubstituted
benzoic and naphthyl carboxylic acids also gave high yields
(4ka-4oa). When starting with unsubstituted benzoic acid
(1p), the double hydroarylation product 4pa' was obtained.
Since the carbonyl group of indanones has been shown not
to be an effective directing group for C–H activation,26 the
second hydroarylation must have occurred while the car-
boxylate group was still intact. Thus, one can conclude that
the Ir enolate formation must be reversible (see Scheme 2,
III ⇌ IV) and the hydroarylation step is faster than Claisen
condensation. After double hydroarylation of 1p, only one
of the ketone side chains can undergo the subsequent
Claisen steps leading to 4pa'.
1
2
3
4
5
6
7
8
Table 3. Substrate scope of 3-arylindanonesa
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[IrCp*Cl2]2
K2CO3, In(OTf)3
tAmylOH/H2O
1
2
4
R2 = Me
R = Me,
R = Et,
R = Ph,
4aa 83%(68%)b
4ba 81%
R = Me,
4ga 71%
R = OMe, 4ha 51%
R = NMe2, 4ia 53%
4ca 63%
R = OCF3, 4da 46%
R = NHAc, 4ja 52%
R = NHPh, 4ea 50%
R = Cl,
4fa 45%
The scope with regard to the α,β-unsaturated ketones was
explored using o-toluic acid as coupling partner. β-Ary-
lated ketones bearing electron‐rich and electron‐poor sub‐
stituents in their o-, m-, or p-position reacted similarly
well, and various functional groups, including CF3, halo,
CN, keto, ester, amide, pyridyl, and sulfonyl moieties were
tolerated. The new catalyst system gives higher yields for
most substrates that can also be converted with the Rh-
based catalyst, but interestingly, cyclic alkenones, which
are optimal for the Rh protocol,20 give unsatisfactory re-
sults (4as-4at).
4ka 73%
4la 54%
4ma 66%
4na 72%
4oa 58%
4pa 30%
4ab 72%
4pa` 33%
R = Cl,
R = Me,
4ah 65%
4ai 77%
4aj 69%c
4ak 48%
R = OMe, 4ac 53%
R = Br,
R = CN,
R = CO2Me,
R = Ph,
R = Ac,
R = CF3,
4ad 64%
4ae 57%
4af 74%
The deacylative reaction variant (B) is not limited to me-
thyl ketones but can be conducted with various long-chain
alkyl, aryl, and even divinyl ketones. At this stage, other
types of electron-deficient alkenes, including acid deriva-
tives or aldehydes, did not give the desired product in ei-
ther protocol (Scheme S6). The reaction was successfully
scaled up to 10 mmol for the example of β-phenyl vinyl ke-
tone (4aa). The key advantage of this synthetic entry to in-
danones is that the α,β-unsaturated ketones are easily ac-
cessible by aldol condensation of methyl ketones with al-
dehydes. This condensation step can even be performed in
situ, which was demonstrated for the example of indanone
4aa (Scheme 3).
R = SO2Me,
4al 75%c
R = F,
4ag 74%
R = CON(Et)2, 4am 65%
4an 60%
4ao 66%
4ap 70%
4aq 64%
Scheme 3. One-pot process from benzaldehyde and
acetone.
4ar 50%c
4as 86%d
4at 90%d
2)
1a (0.5 mmol)
1) K2CO3
[IrCp*Cl2]2, In(OTf)3
tAmylOH/H2O
2u
2v
2w
2x
acetone
Ar, 100 °C, 16 h
4ab 67%
4ab 62%
4aa 65%
4aa 28%
Ar, 140 °C, 16 h
4aa
56%
aReaction conditions: 0.5 mmol of 1, 0.8 mmol of 2, 3 mol%
of [IrCp*Cl2]2, 7.5 mol% of In(OTf)3, 0.2 mmol of K2CO3,
The reaction mechanism was elucidated in a series of ex-
periments (Scheme S1). In the presence of [IrCp*Cl2]2, o-
toluic acid was swiftly deuterated in ortho-position, indi-
cating rapid and reversible C−H bond cleavage. Deuter‐
ium-labelling experiments revealed that the 3-arylin-
danone α-hydrogen originates from the solvent (Scheme
S2).
t
b
0.2 mL of AmOH/H2O (3:1), 140 °C, 16 h. 10 mmol scale.
cusing 5 mol% of [IrCp*Cl2]2. dusing 0.6 mmol of 2.
The functional group tolerance was not tested for this pro-
tocol separately, since it is safe to assume that all com-
pounds that were successfully converted in the deacylative
reaction cascade (protocol B) will also survive this one-step
process. The scope of the deacylative reaction variant (B)
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was added, proceeded much more slowly, indicating that
Page 4 of 7
Scheme 4. Mechanistic investigations.
1
2
3
4
5
6
7
8
3aa interferes with the first reaction step, possibly by its
chelating coordination to the iridium catalyst (Scheme 4c).
a)
K2CO3
tAmylOH/H2O
These experiments suggest the presence of two competing
pathways for the deacylative process, one proceeding via
intermediate 5aa directly to product 4aa, the other via for-
mation of 3aa. The conversion vs time plots in Chart 1 il-
lustrate how the intermediates 5aa (protocol A) or 3aa and
4aa (protocol B) temporarily build up in the non-deacyla-
tive and the deacylative reaction protocols, respectively.
All findings are in excellent agreement with the proposed
mechanism (Scheme 2).
Ar, 140 °C, 16 h
4aa
3aa
1a
<1%
95%
+ In(OTf)3
b)
tAmylOH/H2O
Ar, 140 °C, 16 h
9
5aa
3aa
4aa
3%
30%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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33
34
35
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39
40
41
42
43
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KOAc, no tAmylOH, 150°C
K2CO3
71%
15%
29%
0
0
K2CO3 + [IrCp*Cl2]2
45%
60%
73%
In conclusion, a newly developed Ir-based catalyst system
enables the modular construction of 3-substituted inda-
none moieties from simple benzoic acids, aldehydes, and
alkyl ketones. It fulfills the high expectations raised by the
prototype Rh-based catalyst generation and leads the hy-
droarylation/ Claisen approach to synthetic maturity. Two
complementary reaction protocols provide selective en-
tries to either 2-acyl indanones or their deacylated deriva-
tives.
K2CO3 + In(OTf)3
11%
0%
K2CO3 + [IrCp*Cl2]2 + In(OTf)3
c)
[IrCp*Cl2]2, KOAc
H2O, Ar, 150 °C
1a
2a
5aa
3aa
4aa
88%
recovered
N.D
<10%
2%
3aa (0.5 equiv.)
Chart 1. Yield-time plots for A) acylindanone protocol;
B) deacylative protocol.
ASSOCIATED CONTENT
Supporting Information
2a
1a
5aa
3aa
4aa
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Protocol A: [IrCp*Cl2]2, KOAc, H2O, 150 °C
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
General methods, detailed mechanistic studies, experimental
procedures, synthesis and characterization of products, and
NMR spectra (PDF).
1a (%)
5aa (%)
3aa (%)
4aa (%)
AUTHOR INFORMATION
Corresponding Author
*E-mail: lukas.goossen@rub.de
ORCID
Lukas J. Gooßen: 0000-0002-2547-3037
0 h
2 h
4 h
6 h
8 h
10 h
12 h
14 h
16 h
reaction time
Notes
Protocol B: [IrCp*Cl2]2, K2CO3, In(OTf)3, tAmylOH/H2O, 140 °C
The authors declare no competing financial interest.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ACKNOWLEDGMENT
1a (%)
5aa (%)
3aa (%)
4aa (%)
Funded by the Deutsche Forschungsgemeinschaft (DFG, Ger-
man Research Foundation) under Germany’s Excellence Strat‐
egy – EXC-2033 – Projektnummer 390677874, SFB‐TRR 88
“3MET”, and GO 853/12-1. We thank UMICORE for donating
chemicals, BMBF and the state of NRW (Center of Solvation
Science “ZEMOS”), the CSC (fellowships to G.Z. and Z.H.) for
financial support, and M. Wüstefeld for HRMS measurements.
REFERENCES
0 h
2 h
4 h
6 h
8 h
10 h
12 h
14 h
16 h
reaction time
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why strong bases must be avoided when aiming to form
product 4aa. [IrCp*Cl2]2 and In(OTf)3 both facilitate this
step (Scheme 4b). A control reaction, in which excess 3aa
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ACS Catalysis
TOC
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KOAc
H2O
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[IrCp*Cl2]2
14 examples
41-76% yields
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K2CO3, In(OTf)3
tAmylOH/H2O
R1, R2 = alkyl or Ar
waste-minimized
39 examples
28-90% yields
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broad scope
gram scale
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