Palladium-Catalyzed Direct α-Arylation of Indane-1,3-dione to 2-Substituted Indene-1,3-diones

Article abstract of DOI:10.1021/acs.joc.1c01149

A straightforward and feasible palladium-catalyzed direct α-arylation of indane-1,3-dione to 2-substituted aryl/heteroaryl indene-1,3-diones has been disclosed for the first time. Optimization of reaction conditions identified tBu-XPhos as a preferred ligand for the bis(acetonitrile)dichloropalladium(II) catalyst. A broad spectrum of aryl iodides and aryl triflates containing electron-donating, electron-withdrawing, and sterically hindered substituents gave an excellent yield for the quick access α-arylated 1,3-diones library.

Full text of DOI:10.1021/acs.joc.1c01149

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Palladium-Catalyzed Direct α‑Arylation of Indane-1,3-dione to
2‑Substituted Indene-1,3-diones
Natarajan Tamizharasan, Gurulingappa Hallur,* and Palaniswamy Suresh*
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ABSTRACT: A straightforward and feasible palladium-catalyzed direct α-arylation of indane-1,3-dione to 2-substituted aryl/
t
heteroaryl indene-1,3-diones has been disclosed for the first time. Optimization of reaction conditions identified Bu-XPhos as a
preferred ligand for the bis(acetonitrile)dichloropalladium(II) catalyst. A broad spectrum of aryl iodides and aryl triflates containing
electron-donating, electron-withdrawing, and sterically hindered substituents gave an excellent yield for the quick access α-arylated
1,3-diones library.
Scheme 1. Previously Reported Strategies to Access α-
Arylated Indene-1,3-diones
he C−C bonds forming through metal-catalyzed cross-
T
coupling is one of the prime methodologies and widely
adopted synthetic tools for constructing distinct organic
motifs. α-Arylation is an efficient method for functionalizing
the acidic “α-” C−H bond of carbonyl compounds with aryl
motifs. Over the decades, the α-arylation of carbonyl
compounds emerged as one of the pivotal bond-forming
reactions due to their broad scope in natural products and
clinical molecules.1 Transition metals play a vital role, in α-
arylation of ketones and various EWG functionalized substrates
with alkyl/aryl halides.2 Although numerous α-arylation
reagents have been developed, their applications are limited
because they involve different strategies and transmetalation.3
Furthermore, major efforts toward the α-arylation of aliphatic
enolates4 and cyclic carbonyl compounds have scantly been
reported.5 It reveals that some shortcomings still exist in the
direct α-arylation of cyclic carbonyl compounds. Indane-1,3-
diones, pivotal cyclic carbonyl compounds, are explored as a
key building block for the synthesis of many natural products
and pharmaceuticals.6 Their corresponding α-arylated deriva-
tives 2-aryl indene-1,3-diones serve as the essential synthetic
precursor for various bioactive molecules7 (Figure S1, see
Supporting Information (SI)) with a broad spectrum of
therapeutic properties.8−11 Because of their decisive role in
organic synthesis, some methodologies for the synthesis of
arylated indene-1,3-diones have been reported8,9,12 (Scheme
1). Alkoxide base-catalyzed condensation of aryl aldehyde with
Received: May 17, 2021
https://doi.org/10.1021/acs.joc.1c01149
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© XXXX American Chemical Society
A

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a
Table 1. Optimization of Catalyst and Ligand for the Direct α-Arylation of Indane-1,3-dione
g
entry
ligand
L1−L4
catalyst
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
Pd2(dba)3
PdCl2
(allylPdCl)2
Pd(CH3CN)2Cl2
Pd(OAc)2
base
yield (%) 3f/4
a
1
all four bases
Na2CO3
Cs2CO3
KOtBu
K2CO3
Cs2CO3
KOtBu
K2CO3
K3PO4
Et3N
KOtBu
KOtBu
KOtBu
KOtBu
K3PO4
KOtBu
KOtBu
-/-
-/-
b
2
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
S-Phos (L5)
tBuMePhos (L6)
b
3
16/17
33/32
25/15
17/22
53/13
44/12
28/17
-/-
44/9
47/8
41/11
64/7
20/26
-/-
b
4
b
5
c
6
c
7
c
8
c
9
c
10
11
12
13
14
15
c
c
c
c
d
e
16
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
f
17
S-Phos (L5)
-/-
a
Reaction conditions: Ligands L1−L4 (4 mol %), all four bases (Na2CO3, Cs2CO3, KOtBu, and K2CO3(2.3 equiv), catalyst (4 mol %), total 16
b
reactions, 1,4-dioxane, sealed tube; 80 °C, 20 h. Reaction conditions B: Ligand (4 mol %), catalyst (4 mol %), base (2.3 equiv), 1,4-dioxane, 80
c
°C, 20 h, sealed tube. Reaction conditions C: Ligand (8 mol %), catalyst (4 mol %), base (2.3 equiv), 1,4-dioxane, 110 °C, 12 h, sealed tube.
d
e
Reaction conditions D: Ligand (2.2 mol %), catalyst (1 mol %), base (2.3 equiv), THF, 80 °C, 23 h, sealed tube (ref 5). Reaction conditions E:
f
Catalyst (4 mol %), base (2.3 equiv), 1,4-dioxane, 110 °C, 12 h, sealed tube. Reaction conditions F: 1-Chloro/1-bromo-4-fluorobenzene (1 equiv),
ligand (8 mol %), catalyst (4 mol %), base (2.3 equiv), 1,4-dioxane, 110 °C, 12 h, sealed tube. Isolated yield.
g
phthalide gave aryl-substituted indene-1,3-dione in moderate
yield.8,9 Rhodium-catalyzed synthesis of substituted indene-
1,3-dione13 was achieved through the decomposition of diazo
derivatives. In another attempt, a multistep approach through
oxidative cyclization involving the reaction between 1-(2-
bromophenyl)-2-phenylethanone with tert-butyl isocyanide
formed an intermediate and the arylated indene-1,3-dione
which was obtained through consecutive hydrolysis.14
Though α-arylated indene-1,3-diones have found potential
synthetic applications, however, their access through the
traditional synthetic methods requires multistep synthesis
with an overall low yield. Existing shortcomings prompted us
to develop a reliable methodology to access the 2-aryl indene-
1,3-dione through a direct and facile coupling strategy. Herein,
we report a direct α-arylation of indane-1,3-dione through
intermolecular cross-coupling with aryl iodide using a
palladium catalyst. To the best of our knowledge, no method
has been attempted for the direct α-arylation of aromatic cyclic
1,3-diketones, using Pd(CH3CN)2Cl2 as a catalyst.
To find an optimal reaction condition for the direct α-
arylation of indane-1,3-dione (1), a model reaction was initially
performed with 4-fluoroiodobenzene (2f) in 1,4-dioxane
medium at 80 °C using a palladium catalyst with a series of
ligands (L1−L14, see SI, Scheme S1). These reactions were
screened with different bases, and the results are summarized
in Tables 1 and 2. First, phosphine ligands L1−L4 were
screened with four different bases Cs2CO3, Na2CO3, KOtBu,
and K2CO3 (Table 1, entry 1), where weak bases were chosen
owing to the mild acidic nature (pKa 10) of the indane-1,3-
dione (1). Ligands (L1−L4) screened with four different base
Table 2. Screening of Ligands for Palladium-Catalyzed
Direct α-Arylation of Indane-1,3-dione (1)
a
b
entry
ligand
yield (%) 3f/4
1
2
3
S-Phos (L5)
64/7
68/21
42/15
93/-
tBuMePhos (L6)
John Phos (L7)
tBu-XPhos (L8)
4
t
5
6
Me4 Bu- XPhos (L9)
30/11
43/-
XPhos (L10)
7
8
9
10
Brett Phos (L11)
Dave Phos (L12)
RuPhos (L13)
CM-Phos (L14)
56/-
14/6
36/14
39/14
a
Reaction conditions: Ligand (8 mol %), Pd(CH3CN)2Cl2 (4 mol
%), KOtBu (2.3 equiv), 1,4-dioxane, 110 °C, 12 h, sealed tube.
b
Isolated yield.
combinations were inactive toward this reaction without any
notable conversion. However, under the identical condition,
ligand L5, screened with the same four bases, gave slightly
better yields of 3f (entries 4 and 5, Table 1) with KOtBu
(33%) and K2CO3(25%) along with the quantitative amount
(32% and 15%) of condensation product 4.
From these encouraging results, further optimization was
carried to enhance the α-arylated product and suppress or
prevent the undesired condensation product (4). From the
literature, it is known that the 2:1 ligand and catalyst ratio was
optimal for the arylation of enolates.2b,15 On the basis of that,
the loading amount of L5 was increased from 4 mol % to 8 mol
B
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%, maintaining the same catalyst load (4 mol %). Meanwhile,
the reaction temperature was increased to 110 °C and the time
was reduced to 12 h. A marginal enhancement in the α-
arylated product and concomitant decrease of condensation
was observed with KOtBu (entry 7, Table 1).
Table 3. Palladium-Catalyzed α-Arylation of Indane-1,3-
dione with Aryl Iodides
a
The screening results in Table 1 showed low to a moderate
yield of the desired product (3f), we speculated this could be
due to catalyst’s poor activation. In order to address this, we
next tried with the direct source of Pd(0) catalyst of Pd2(dba)3
(entry 11, Table 1). However, the yield remained unchanged.
Further, screening with other palladium(II) catalysts, such as
PdCl2, (allylPdCl)2, and Pd(CH3CN)2Cl2, indicated that the
latter one suppressed the formation of the condensation
product 4 (entry 14, Table 1) and considerably enhanced the
yield (64%) of 3f. Previously reported conditions were not
encouraging for the present arylation (entry 15, Table 1); also,
the reaction is highly inert only with a palladium source and
without ligand (entry 16, Table 1). This inspiring result
encouraged us to screen with other biaryl phosphine ligands to
further fine-tune the selectivity toward the desired product (3f)
without condensation product (4). Two sets of readily
available ligands such as di-tert-butyl biaryl phosphines ligands
(L6−L9) and dicyclohexylbiarylphosphines ligands (L10−
L14) were further screened with Pd(CH3CN)2Cl2. Among the
screened ligands, L8, L10, and L11, selectively yielded the
desired α-arylated product 3f and without formation of
condensation product. The ligand 2-di-tert-butylphosphino-
2′,4′,6′-triisopropylbiphenyl (L8) gave the α-arylated product
3f to our delight selectively with the maximum yield 93%
(Table 2, entry 4).
The ligand screening results revealed that the substituents
present on the tBu-XPhos (L8) have played a crucial role than
the substituents of dicyclohexyl biaryl phosphine ligands (L10
and L11). The enhanced reactivity and selectivity of the
palladium catalyst were rationalized through the boom in the
electron density at the metal center, which fastened the
oxidative addition and reductive elimination step, also strongly
influenced the side reactions, and eliminated the condensation
product. Finally, in the screening studies, the role of solvents
(Table S1, see SI) was also examined and 1,4-dioxane was
chosen as an appropriate solvent under the screened
conditions for both selectivity and yield. From the above-
screened parameters, the optimum reaction condition for the
smooth α-arylation of indane-1,3-dione was found to be using
a
Reaction conditions: Indane-1,3-dione (1.0 equiv), aryl iodide (1.0
equiv), KOtBu (2.3 equiv), tBu-XPhos (0.08 equiv), Pd(CH3CN)2Cl2
(0.04 equiv), 1,4-dioxane, 110 °C, 12 h, sealed tube. All are isolated
yields. 5 g scale reaction.
b
Conversely, in the case of 1-bromo-4-iodo-2-methylbenzene
(2l), the yield was drastically decreased to 33% (Table 3, 3l)
owing to the electronic reinforcement between bromo and
methyl substituents present ortho to each other, which
decreased the leaving nature of the iodo group and decreased
the reactivity toward the oxidative addition. Notably, the iodo
coupling’s selectivity was specifically favored than bromo
coupling and no traces of bromo coupled product was
observed. Disubstituted aryl iodide with both electron-
releasing and electron-withdrawing substitutes had undergone
the arylation (3m−3o and 3q) with a mild drop in the yield.
However, the electronic reinforcement between the
substitutes did not affect the yield. Similarly, the dihalo
substituents on aryl iodides gave good yield (3p and 3r)
irrespective of their electronic nature. 1,3-Difluoro-2-iodoben-
zene (2s) gave a relatively moderate yield for 3s (56%)
compared to 3r (85%) owing to the steric hindrance of both
ortho-substituted fluoro groups. Finally, the scope of heteroaryl
iodide was also attempted with iodopyridines. 3-Iodopyridine
(2t) gave a low yield (3t, 12%); meanwhile, with another
heteroaryl iodide, 4-iodo pyridine (2u) gave a moderate yield
(3u, 52%). From the NMR analysis, both were confirmed that
they existed as their corresponding enol form. Next, a
substituted, 5-methoxy indane-1,3-dione also gave the
corresponding products (3v and 3w) with good yields.
Further, the scope of this reaction extended to one more
t
Pd(CH3CN)2Cl2 as a catalyst with ligand Bu-XPhos in 1,4-
dioxane at 110 °C for 12 h.
With the optimized reaction condition for α-arylation of
indane-1,3-dione (1) in hand, we then probed the substrate
t
scope using the Pd(CH3CN)2Cl2 and Bu-XPhos catalytic
system. We studied a wide range of activated and non-activated
aryl iodides, and the results are shown in Table 3. The electron
neutral (4-H) and electron-rich (4-Me, 2,5-diMe, and 2-OMe)
substituted aryl iodides had undergone α-arylation with 1 to
the corresponding product in good to excellent yield (82−
89%, Table 3, 3a−3c and 3h). Aryl iodides with electron-
withdrawing substituents such as chloro (3d), ester (3e), 4-
fluoro (3f), and 3-fluoro (3g) were also compatible with
current reaction conditions with good yield (84−93%).
Further, spectra of aryl iodides with disubstituent (3i−3s)
were also tested. 4-Methyliodobenzene having 2-chloro, 3-
chloro, and 2-fluoro substitutes yielded the corresponding α-
arylated products 3i−3k with good yield without any
electronic and steric influences from the halo substituents.
C
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diketo compound dimedone, which reacted smoothly with aryl
iodide and gave the arylated product (3x, 89%) in good yield.
Indeed, from the wide reactivity of aryl iodides, it clearly
demonstrates that, in the palladium-catalyzed α-arylation of
indane-1,3-dione, substituents’ electronic nature and the steric
factors were not more influenced in the reaction conversion.
Furthermore, the optimized conditions strongly favored the
smooth and selective formation of the α-arylated products.
Furthermore, the present catalytic system’s scope was also
extended with the other electrophiles such as aryl chlorides and
bromide and aryl triflates under the optimized reaction
conditions. As observed in the above substrate scope (Table
3, entries 3d and 3l), aryl chlorides and aryl bromides were
highly inert even after an extended reaction time and
temperature.
Scheme 2. Plausible Mechanism for Palladium-Catalyzed
Direct α-Arylation of Indane-1,3-dione
On the contrary, electrophile phenyl triflate (5a) smoothly
underwent the coupling with 1 under a similar reaction
condition and yielded 3a (Table 4) in excellent yield (91%).
Table 4. Palladium-Catalyzed α-Arylation of Indane-1,3-
a
dione with Aryl Triflates
give the desired coupling product and regenerates the Pd(0)
complex for the next catalytic cycle.
In summary, we have demonstrated the first palladium-
catalyzed direct α-arylation of indane-1,3-dione (1) using aryl
iodides as electrophiles. The combination of the Pd-
t
(CH3CN)2Cl2 and Bu-XPhos as a suitable catalytic system
for the present α-arylation exhibited excellent product
selectivity. The above combination selectively yields only the
coupling product over the other ligands and palladium catalyst
combinations and avoids formation of the condensation
product. This catalytic system is highly compatible with a
wide range of aryl iodides and aryl triflates bearing electron-
rich, electron-neutral, and electron-poor substituents, which
are smoothly coupled with the indane-1,3-dione and other
cyclic 1,3-dione systems. Further, the optimized catalytic
system is feasible with a gram-scale reaction. Further
investigation on the arylation of other sterically hindered
diverse 1,3-diones using the present catalytic system is now
underway.
a
Reaction conditions: Indane-1,3-dione (1.0 equiv), aryl triflate (1.0
equiv), KOtBu (2.3 equiv), tBu-XPhos (0.08 equiv), Pd(CH3CN)2Cl2
(0.04 equiv), 1,4-dioxane, 110 °C, 12 h, sealed tube. All are isolated
yields.
Then it was extended with diverse aryl triflates 5a−5g (Table
4). Electron neutral aryl triflates gave the corresponding
coupled products 3a and 3ab in excellent yield. Similar
behavior was also observed with electron-releasing (3y−3z)
substitutes; conversely, electron-withdrawing substituents
(3aa) gave moderate yield (63%). Heteroaryl-substituted
bicyclic systems underwent the coupling with 1 and gave the
α-arylated product 3ac−3ae from good to excellent (74−92%)
yield.
GENERAL PROCEDURE FOR
■
PALLADIUM-CATALYZED DIRECT α-ARYLATION
OF INDANE-1,3-DIONE
To a stirred solution of 1H-indene-1,3(2H)-dione derivative (0.68
mmol) in dry dioxane (4 mL) were added substituted iodobenzene
(0.68 mmol), tBu-XPhos (0.054 mmol), and Pd(CH3CN)2Cl2 (0.027
mmol). The resulting mixture was purged with argon gas for 15 min.
Potassium tert-butoxide (1.57 mmol) was added into the reaction
mixture and stirred at 110 °C (preheated oil bath) for 12 h in a sealed
tube. The reaction was monitored by TLC. The reaction mixture was
cooled to room temperature, filtered through a Celite bed, and
washed with 1,4-dioxane (10 mL), and the filtrate was removed. All
the nonpolar impurities and volatiles are removed. The Celite bed was
washed with methanol (50 mL). The filtrate was concentrated under
high vacuum to get a crude compound. The crude residue was
purified through combi-flash column chromatography using silica gel
cartridges (0−20% MeOH in EtOAc) which afforded the α-arylated
substituted indane-1,3-dione derivatives.
With the help of the observed experimental results and from
the previous literature report, a possible mechanism could be
proposed for the first palladium-catalyzed direct α-arylation of
indane-1,3-dione (1). As shown in Scheme 2, initially, the
palladium catalyst Pd(CH3CN)2Cl2 forms a Pd0 (I) complex
t
with Bu-XPhos. Then, it undergoes oxidative addition with
aryl iodide to form the complex II. Meanwhile, the diketone 1
gets deprotonated by the base KOtBu, and the resulting
carbanion coordinates with II and forms complex III. Owing
to the presence of two carbonyl groups at 1,3-positions in
compound 1, it undergoes keto-enol tautomerism, and there
exists a possibility of two types of complexes IV and V. In the
next step, either IV or V undergoes reductive elimination, to
D
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2-Phenyl-1H-indene-1,3(2H)-dione: (3a).8 White solid (0.135
g, 89%); m.p.: 148−149 °C. H NMR (400 MHz, CDCl3): δ 8.07−
2-(2-Fluoro-4-methylphenyl)-1H-indene-1,3(2H)-dione:
1
1
(3k). White solid (0.135 g, 78%); m.p.: 180−181 °C. H NMR (400
MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.92−7.90 (m, 2H), 6.82 (d,
8.06 (m, 2H), 7.91−7.90 (m, 2H), 7.36−7.28 (m, 3H), 7.20−7.18
(m, 2H), 4.26 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 198.2,
142.7, 135.9, 133.2, 128.9, 128.7, 127.8, 123.7, 59.8. Mass (ESI):
221.0 (M − 1).
1H, J = 9.6 Hz), 6.78 (s, 1H), 6.71 (d, 1H, J = 9.2 Hz), 4.2 (s, 1H),
2.31 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.6, 162.9 (JCF
=
244.8 Hz), 142.6, 141.1 (JCF = 8.5 Hz), 136.1, 134.7 (JCF = 8.5 Hz),
125.2 (JCF = 2.4 Hz), 123.8, 115.6 (JCF = 20.9 Hz), 112.9 (JCF = 22.4
Hz), 59.3, 21.3. HRMS (ESI) m/z: [M + H]+ calculated for
C16H11FO2 + H+, 255.0815; found 255.0815.
2-(p-Tolyl)-1H-indene-1,3(2H)-dione: (3b).9 White solid (0.139
1
g, 86%); m.p.: 143−145 °C. H NMR (400 MHz, CDCl3) δ 8.06−
8.05 (m, 2H), 7.90−7.89 (m, 2H), 7.15 (d, 2H, J = 7.6 Hz), 7.06 (d,
2H, J = 7.6 Hz), 4.22 (s, 1H), 2.32 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 198.5, 142.7, 137.6, 135.9, 130.1, 129.7, 128.6, 123.7,
59.6, 21.1. Mass (ESI): 235.0 (M − 1).
2-(4-Bromo-3-methylphenyl)-1H-indene-1,3(2H)-dione: (3l).
1
Pale yellow solid (0.071 g, 33%); m.p.: 201−203 °C. H NMR (400
MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.92−7.90 (m, 2H), 7.50 (d,
1H, J = 8.4 Hz), 7.05 (s, 1H), 6.87 (d, 1H, J = 7.6 Hz), 4.19 (s, 1H),
2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.8, 142.5,
139.3, 138.6, 136.1, 132.9, 132.2, 131.1, 127.7, 123.8, 59.2, 22.9.
HRMS (ESI) m/z: [M + H]+ calculated for C16H11BrO2 + H+,
315.0015; found 315.0014.
2-(2-Methoxyphenyl)-1H-indene-1,3(2H)-dione: (3c).9 White
solid (0.142 g, 82%); m.p.: 178−179 °C. 1H NMR (400 MHz,
CDCl3) δ 8.03−8.01 (m, 2H), 7.87−7.85 (m, 2H), 7.32−7.28 (m,
2H), 7.00 (t, 1H, J = 7.6 Hz), 6.79 (d, 1H, J = 8 Hz), 4.16 (s, 1H),
3.44 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 199.1, 156.5,
141.7, 135.3, 132.7, 129.7, 123.1, 122.9, 121.3, 110.9, 58.7, 55.3. Mass
(ESI): 253.0 (M + 1).
2-(2-Methoxy-4-nitrophenyl)-1H-indene-1,3(2H)-dione:
1
(3m). Pale yellow color solid (0.169 g, 83%); m.p.: 125−127 °C. H
2-(4-Chlorophenyl)-1H-indene-1,3(2H)-dione: (3d).9 Yellow
solid (0.160 g, 91%); m.p.: 145−147 °C. 1H NMR (400 MHz,
CDCl3) δ 8.08−8.06 (m, 2H), 7.93−7.90 (m, 2H), 7.29−7.28 (m,
2H), 7.19 (s, 1H), 7.10 (s, 1H), 4.23 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 197.7, 142.5, 136.1, 133.9, 131.4, 130.1, 129.2, 123.8,
58.9. Mass (ESI): 255.0 (M − 1).
NMR (400 MHz, CDCl3) δ 8.06−8.04 (m, 2H), 7.92−7.91 (m, 3H),
7.66 (s, 1H), 7.42 (d, 1H, J = 8 Hz), 4.33 (s, 1H), 3.58 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 197.3, 157.0, 149.1, 141.6,
135.8, 133.1, 130.1, 123.4, 116.4, 105.9, 58.5, 56.0. HRMS (ESI) m/z:
[M + H]+ calculated for C16H12NO5 + H+, 298.0709; found 298.0707.
2-(2-Methyl-4-(trifluoromethoxy)phenyl)-1H-indene-
1,3(2H)-dione: (3n). Gray color solid (0.174 g, 79%); m.p.: 209−
Methyl 3-(1,3-Dioxo-2,3-dihydro-1H-inden-2-yl)benzoate:
(3e). Pale brown solid (0.164 g, 86%); m.p.: 131−132 °C. 1H
NMR (400 MHz, CDCl3) δ 8.09−8.07 (m, 2H), 8.00 (d, 1H, J = 7.2
Hz), 7.93−7.91 (m, 2H), 7.85 (s, 1H), 7.47−7.40 (m, 2H), 4.33 (s,
1H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.6, 166.5,
142.5, 136.2, 133.6, 133.4, 130.9, 129.6, 129.9, 129.1, 123.9, 59.5,
52.2. HRMS (ESI) m/z: [M − H]− calculated for C17H12O4,
279.0651; found 279.0675.
1
211 °C. H NMR (400 MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.93−
7.91 (m, 2H), 7.10 (s, 1H), 6.98 (d, 1H, J = 8.4 Hz), 6.91 (d, 1H, J =
8.4 Hz), 4.51 (s, 1H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 198.0, 142.7, 142.3, 139.9, 136.1, 130.9, 130.4, 123.7, 123.2,
120.4 (JCF = 255.7 Hz), 118.56, 58.27, 20.36. HRMS (ESI) m/z: [M
− H]− calculated for C17H11F3O3, 319.0577; found 319.0578.
2-(2-Chloro-4-(trifluoromethyl)phenyl)-1H-indene-1,3(2H)-
1
dione: (3o). Off-white solid (0.169 g, 76%); m.p.: 145−146 °C. H
2-(4-Fluorophenyl)-1H-indene-1,3(2H)-dione: (3f).8 Yellow
solid (0.153 g, 93%), m.p.: 116−117 °C. 1H NMR (400 MHz,
CDCl3) δ 8.08−8.06 (m, 2H), 7.92−7.91 (m, 2H), 7.19−7.16 (m,
2H), 7.07−7.02 (m, 2H), 4.25 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 197.9, 162.4 (JCF = 246.4 Hz), 142.4, 135.9 (JCF = 24.8
NMR (400 MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.93−7.91 (m, 2H),
7.67 (s, 1H), 7.54 (d, 1H, J = 8 Hz), 7.32 (d, 1H, J = 8 Hz), 4.65 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.9, 141.8, 136.1, 135.8,
134.9, 133.1, 132.1 (JCF = 33.3 Hz), 126.9, 124.3 (JCF = 31 Hz),
123.8, 120.5 (JCF = 251.2 Hz), 60.4. HRMS (ESI) m/z: [M + H]+
calculated for C16H8ClF3O2 + H+, 325.0238; found 325.0238.
2-(2,3-Dichlorophenyl)-1H-indene-1,3(2H)-dione: (3p). Pale
yellow color solid (0.158 g, 79%); m.p.: 213−214 °C. 1H NMR (400
MHz, CDCl3) δ 8.07−8.05 (m, 2H), 7.92−7.90 (m, 2H), 7.47 (d,
1H, J = 8 Hz), 7.22 (d, 1H, J = 8 Hz), 7.12 (d, 1H, J = 6.8 Hz), 4.60
(s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 196.5, 141.7, 135.9,
134.0, 133.8, 131.1, 130.5, 130.4, 127.7, 123.7, 61.3. HRMS (ESI) m/
z: [M + H]+ calculated for C15H8Cl2O2 + H+, 290.9974; found
290.9976.
Hz), 130.4 (JCF = 7.7 Hz), 128.7 (JCF = 3.1 Hz), 123.8, 115.9 (JCF
=
21.7 Hz), 58.9. Mass (ESI): 241.0 (M + 1).
2-(3-Fluorophenyl)-1H-indene-1,3(2H)-dione: (3g).9 White
solid (0.138 g, 84%); m.p.: 158−160 °C. 1H NMR (400 MHz,
CDCl3) δ 8.09−8.06 (m, 2H), 7.92−7.90 (m, 2H), 7.35−7.31 (m,
1H), 7.03−6.99 (m, 2H), 6.94−6.92 (m, 1H), 4.26 (s, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 197.4, 162.9 (JCF = 245.6 Hz), 142.5,
136.1, 134.9 (JCF = 7.7 Hz), 130.4 (JCF = 8.5 Hz), 124.5 (JCF = 3.1
Hz), 123.9, 115.9 (JCF = 22.5 Hz), 114.9 (JCF = 20.9 Hz), 59.2. Mass
(ESI): 239.0 (M − 1).
2-(3-Fluoro-5-methylphenyl)-1H-indene-1,3(2H)-dione:
2-(2,5-Dimethylphenyl)-1H-indene-1,3(2H)-dione: (3h).16a
White solid (0.142 g, 83%); m.p.: 156−157 °C. 1H NMR (400
MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.91−7.89 (m, 2H), 7.11 (d,
1H, J = 7.6 Hz), 7.01 (d, 1H, J = 7.2 Hz), 6.68 (s, 1H), 4.46 (s, 1H),
2.26 (s, 3H), 2.22 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
198.8, 142.5, 137.1, 135.8, 134.2, 132.1, 130.8, 129.9, 128.9, 123.6,
59.0, 20.8, 19.8. Mass (ESI): 251.1 (M + 1).
(3q).16b Pale yellow solid (0.142 g, 82%); m.p.: 182−183 °C. H
1
NMR (400 MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.92−7.90 (m, 2H),
6.82 (d, 1H, J = 9.2 Hz), 6.78 (s, 1H), 6.71 (d, 1H, J = 9.2 Hz), 4.20
(s, 1H), 2.31 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.6,
162.9 (JCF = 245.6 Hz), 142.6, 141.1 (JCF = 7.7 Hz), 136.1, 134.7 (JCF
= 8.5 Hz), 125.2 (JCF = 2.4 Hz), 123.8, 115.6 (JCF = 20.9 Hz), 112.9
(JCF = 22.5 Hz), 59.3, 21.3. Mass (ESI): 253.1 (M − 1).
2-(3,5-Difluorophenyl)-1H-indene-1,3(2H)-dione: (3r).16b
White solid (0.15 g, 85%); m.p.: 135−137 °C. 1H NMR (400
MHz, CDCl3) δ 8.09−8.07 (m, 2H), 7.94−7.91 (m, 2H), 6.80−6.74
(m, 3H), 4.24 (s, 1H). 13C{1H} NMR (100 MHz, DMSO-d6) δ
185.7, 162.8 (JCF = 240.9 Hz), 162.7 (JCF = 241.7 Hz), 137.2, 137.1,
136.9, 136.7, 132.1, 120.3, 108.5, 104.5, 100.1. Mass (ESI): 257.0 (M
− 1).
2-(3-Chloro-4-methylphenyl)-1H-indene-1,3(2H)-dione: (3i).
Brown solid (0.162 g, 88%); m.p.: 116−117 °C. 1H NMR (400 MHz,
CDCl3) δ 8.08−8.06 (m, 2H), 7.92−7.90 (m, 2H), 7.20 (d, 1H, J =
7.6 Hz), 7.17 (s, 1H), 7.00 (d, 1H, J = 8 Hz), 4.20 (s, 1H), 2.34 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.7, 142.5, 136.1, 135.8,
134.8, 131.9, 131.4, 129.2, 127.1, 123.8, 58.9, 19.7. HRMS (ESI) m/z:
[M − H]− calculated for C16H11ClO2, 269.0363; found 269.0378.
2-(2-Chloro-4-methylphenyl)-1H-indene-1,3(2H)-dione: (3j).
2-(2,6-Difluorophenyl)-1H-indene-1,3(2H)-dione: (3s).16c
White solid (0.099 g, 56%); m.p.: 134−136 °C. 1H NMR (400
MHz, CDCl3) δ 8.06 (s, 2H), 7.91 (s, 2H), 7.31 (t, 1H, J = 7.2 Hz),
6.93 (s, 2H), 4.70 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
196.32, 161.50 (JCF = 250 Hz), 141.76, 135.91, 130.15 (JCF = 20.2
Hz), 123.66, 111.38 (JCF = 2.6 Hz), 110.09 (JCF = 38.8 Hz), 50.63.
Mass (ESI): 257.1 (M − 1).
1
Pale yellow solid (0.147 g, 80%); m.p.: 203−204 °C. H NMR (400
MHz, CDCl3) δ 8.08−8.06 (m, 2H), 7.93−7.91 (m, 2H), 7.18−7.17
(m, 2H), 6.86 (s, 1H), 4.47 (s, 1H), 2.29 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 197.8, 142.3, 136.1, 133.9, 132.9, 132.1, 131.8,
129.0, 128.1, 123.74, 58.6, 19.8. HRMS (ESI) m/z: [M − H]−
calculated for C16H11ClO2, 269.0363; found 269.0362.
E
https://doi.org/10.1021/acs.joc.1c01149
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
3-Hydroxy-2-(pyridin-3-yl)-1H-inden-1-one: (3t).16b Orange
color solid (0.018 g, 12%); m.p.: 259−260 °C. H NMR (400 MHz,
1H), 6.90 (d, 1H, J = 8.4 Hz), 6.75 (d, 1H, J = 8 Hz), 4.55 (t, 2H, J =
8.8 Hz), 4.18 (s, 1H), 3.17 (t, 2H, J = 8.8 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ 198.8, 159.9, 142.6, 135.9, 128.6, 127.9, 125.3, 125.0,
123.7, 109.8, 71.3, 59.4, 29.7. HRMS (ESI) m/z: [M + Na]+
calculated for C17H12O3 + Na+, 287.0679; found 287.0688.
2-(Chroman-6-yl)-1H-indene-1,3(2H)-dione: (3ad). Red color
solid (0.170 g, 89%); m.p.: 117−118 °C. 1H NMR (400 MHz,
CDCl3) δ 8.07−8.05 (m, 2H), 7.90−7.88 (m, 2H), 6.90−6.81 (m,
2H), 6.75 (d, 1H, J = 8.4 Hz), 4.16−4.14 (m, 3H), 2.74 (t, 2H, J = 6
Hz), 2.00−1.94 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 198.8,
154.7, 142.7, 135.9, 130.1, 127.5, 124.6, 123.7, 122.8, 117.4, 66.5,
59.3, 25.0, 22.2. HRMS (ESI) m/z: [M + Na]+ calculated for
C18H14O3 + Na+, 301.0835; found 301.0832.
1
DMSO-d6) δ 15.01 (br, 1H), 9.71 (s, 1H), 9.44 (d, 1H, J = 8.4 Hz),
8.20 (d, 1H, J = 5.2 Hz), 7.78 (q, 1H, J = 8.4 Hz), 7.38 (dd, 2H, J =
5.2 Hz, 4.8 Hz), 7.30 (dd, 2H, J = 4.8 Hz, 5.2 Hz). 13C{1H} NMR
(100 MHz, DMSO-d6) δ 189.9, 140.5, 139.9, 138.18, 137.7, 136.0,
133.5, 131.9, 131.3, 126.8, 125.7, 124.8, 119.1, 97.7. Mass (ESI):
222.0 (M − 1).
3-Hydroxy-2-(pyridin-4-yl)-1H-inden-1-one (3u).16d Orange
1
color solid (0.079 g, 52%); m.p.: >280 °C. H NMR (400 MHz,
DMSO-d6) δ 13.16 (br, 1H), 8.72 (d, 2H, J = 7.2 Hz), 8.17 (d, 2H, J
= 6.8 Hz), 7.54−7.46 (m, 4H). 13C{1H} NMR (100 MHz, DMSO-
d6) δ 191.4, 151.2, 140.1, 138.4, 132.3, 119.9, 115.2, 101.8. Mass
(ESI): 223.0 (M + 1).
2-(2-Oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-indene-
5-Methoxy-2-phenyl-1H-indene-1,3(2H)-dione (3v).16e Pale
yellow solid (0.122 g, 85%); m.p.: 182−184 °C. 1H NMR (400 MHz,
CDCl3) δ 7.98 (d, 1H, J = 8.4 Hz), 7.41−7.29 (m, 5H), 7.18 (d, 2H, J
= 6.8 Hz), 4.24 (s, 1H), 3.98 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 198.4, 196.5, 166.2, 145.4, 136.2, 133.5, 128.9, 128.6, 127.7,
125.4, 124.8, 104.9, 60.1, 56.2. Mass (ESI): 253.1 (M + 1).
2-(4-Fluorophenyl)-5-methoxy-1H-indene-1,3(2H)-dione
1,3(2H)-dione: (3ae). Pale yellow color solid (0.147 g, 74%); m.p.:
1
288−289 °C. H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.93
(d, 4H, J = 3.6 Hz), 6.79−6.74 (m, 3H), 2.74−2.72 (m, 2H), 2.39 (t,
2H, J = 7.6 Hz). 13C{1H} NMR (100 MHz, DMSO-d6) δ 170.6,
139.2, 137.2, 129.7, 129.2, 124.2, 123.3, 123.1, 114.7, 64.0, 30.7, 25.4.
HRMS (ESI) m/z: [M − H]− calculated for C18H13NO3, 290.0811;
found 290.0832.
[1,2′-Biindenylidene]-1′,3,3′(2H)-trione: (4).16g Pale yellow
solid; 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J = 8.4 Hz, 1H), 8.04−
8.02 (m, 1H), 7.99−7.94 (m, 2H), 7.88−7.79 (m, 3H), 7.75 (t, 1H, J
= 14.8 Hz), 4.17 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 200.9,
191.0, 189.3. 155.4, 145.9, 141.7, 141.3, 140.4, 135.4, 135.3, 131.7,
125.9, 123.5, 123.4, 123.1, 43.4. Mass (ESI): 273.0 (M − 1).
1
(3w). Pale pink solid (0.134 g, 87.5%); m.p.: 148−151 °C. H NMR
(400 MHz, CDCl3) δ 7.98 (d, 1H, J = 7.6 Hz), 7.41 (s, 2H), 7.18−
7.15 (m, 2H), 7.03 (t, 2H, J = 8.4 Hz), 4.22 (s, 1H), 3.98 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 198.2, 196.3, 166.3, 162.3 (JCF
=
245 Hz), 145.2, 136.0, 130.2 (JCF = 8 Hz), 129.07 (JCF = 4 Hz),
125.51, 124.99, 116.0 (JCF = 22 Hz), 105.0, 59.2, 56.2. HRMS (ESI)
m/z: [M + H]+ calculated for C16H11FO3 + H+, 271.0765; found
271.0759.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01149.
■
sı
6-Hydroxy-4,4-dimethyl-4,5-dihydro-[1,1′-biphenyl]-2(3H)-
one (3x).16f Off-white solid (0.137 g, 89%); m.p.: 195−197 °C. H
1
NMR (400 MHz, CDCl3) δ 7.45 (t, 2H, J = 8 Hz), 7.36 (t, 1H, J = 4
Hz), 7.20 (d, 2H, J = 4 Hz), 5.99 (br, 1H), 2.49 (s, 2H), 2.38 (s, 2H),
1.17 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 204.8, 130.8,
130.6, 129.7, 129.2, 128.1, 127.0, 116.8, 53.8, 52.2, 31.7, 28.3. Mass
(ESI): 217.0 (M + 1).
Experimental details and spectral characterization of all
compounds (PDF)
2-(3-Propylphenyl)-1H-indene-1,3(2H)-dione: (3y). Red color
solid (0.16 g, 88%); m.p.: 68−69 °C. 1H NMR (400 MHz, CDCl3) δ
8.08−8.06 (m, 2H), 7.91−7.89 (m, 2H), 7.22 (s, 1H), 7.12−7.10 (m,
1H), 6.99−6.96 (m, 2H), 4.22 (s, 1H), 2.55 (t, 2H, J = 7.6 Hz),
1.66−1.60 (m, 2H), 0.92 (t, 3H, J = 7.2 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ 198.5, 143.5, 142.7, 135.9, 132.9, 128.9, 128.8, 128.0,
125.9, 123.8, 59.9, 37.9, 24.4, 13.8. HRMS (ESI) m/z: [M + H]+
calculated for C18H17O2, 265.1223; found 265.1223.
2-(2-Methoxy-4-methylphenyl)-1H-indene-1,3(2H)-dione:
(3z). Yellow solid (0.157 g, 86%); m.p.: 212−213 °C. 1H NMR (400
MHz, CDCl3) δ 8.03−8.01 (m, 2H), 7.86−7.84 (m, 2H), 7.13 (d,
1H, J = 7.2 Hz), 6.81 (d, 1H, J = 7.2 Hz), 6.61 (s, 1H), 4.12 (s, 1H),
3.42 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
199.4, 156.3, 141.7, 139.9, 135.2, 132.4, 123.1, 121.9, 119.9, 111.9,
58.4, 55.2, 21.6. HRMS (ESI) m/z: [M + Na]+ calculated for
C17H14O3 + Na+, 289.0835; found 289.0836.
AUTHOR INFORMATION
Corresponding Authors
■
Gurulingappa Hallur − Medicinal Chemistry Department,
Jubilant Biosys Ltd., Bangalore 560022 Karnataka, India;
Phone: +91-8066628642; Email: Gurulingappa.hallur@
jubilantbiosys.com
Palaniswamy Suresh − Supramolecular and Catalysis Lab,
Department of Natural Products Chemistry, School of
Chemistry, Madurai Kamaraj University, Madurai 625021
Tamil Nadu, India; orcid.org/0000-0002-2827-8552;
Phone: +91-9790296673; Email: ghemistry@gmail.com,
suresh.chem@mkuniversity.ac.in
Author
Natarajan Tamizharasan − Supramolecular and Catalysis
Lab, Department of Natural Products Chemistry, School of
Chemistry, Madurai Kamaraj University, Madurai 625021
Tamil Nadu, India; Medicinal Chemistry Department,
Jubilant Biosys Ltd., Bangalore 560022 Karnataka, India
2-(4-Acetyl-3-methylphenyl)-1H-indene-1,3(2H)-dione:
1
(3aa). Red color solid (0.123 g, 63%); m.p.: 209−211 °C. H NMR
(400 MHz, CDCl3and drop of DMSO-d6) δ 8.01 (s, 1H), 7.87 (s,
2H), 7.62 (d, 1H, J = 8.4 Hz), 7.04 (d, 1H, J = 8 Hz), 6.99 (s, 1H),
4.23 (s, 1H), 2.48 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz,
DMSO-d6) δ 200.7, 185.5, 137.7, 136.8, 133.6, 131.9, 130.4, 129.8,
124.1, 122.7, 120.1, 119.5, 116.3, 106.2, 29.7, 22.3. HRMS (ESI) m/z:
[M + H]+ calculated for C18H14O3 + H+, 279.1015; found 279.1019.
2-(Naphthalen-1-yl)-1H-indene-1,3(2H)-dione: (3ab).7e Pale
yellow solid (0.170 g, 91%); m.p.: 217−218 °C. 1H NMR (400 MHz,
CDCl3) δ 8.12 (s, 2H), 7.95 (s, 2H), 7.88−7.83 (m, 2H), 7.75 (s,
1H), 7.48−7.41 (m, 3H), 7.19 (s, 1H), 4.98 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 198.3, 142.3, 136.0, 134.3, 132.1, 130.1, 128.9,
128.8, 127.7, 126.7, 126.0, 125.3, 123.9, 123.8, 58.5. Mass (ESI):
271.1 (M − 1).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01149
Author Contributions
These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Jubilant Biosys Ltd., Bangalore for supporting and
funding in completion of this work. Dr. P. S. gratefully
■
2-(2,3-Dihydrobenzofuran-5-yl)-1H-indene-1,3(2H)-dione:
(3ac). White solid (0.166 g, 92%); m.p.: 147−148 °C. 1H NMR (400
MHz, CDCl3) δ 8.07−8.06 (m, 2H), 7.91−7.90 (m, 2H), 6.99 (s,
F
https://doi.org/10.1021/acs.joc.1c01149
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(5) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. Highly active
and selective catalysts for the formation of α-aryl ketones. J. Am.
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acknowledges SERB, CSIR, and DST-FIST (SR/FST/CS-II/
2017/35(C)) for financial and instrument (LC-MS and NMR)
support.
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Catalyzed Arylative Cyclization of Alkynones by 1,4-Iridium
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G. J.; Wang, W.; Lee, E.; Ritter, T. A Dinuclear Palladium Catalyst for
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