A method for C2 acylation of 1,3-indandiones

Article abstract of DOI:10.1016/j.tet.2018.04.041

The 1,3-indandione scaffold is an important structural motif used in the preparation of a large number of industrial chemical and pharmaceutical compounds. However, few approaches allow for the direct C2 acylation on these building blocks. A method was developed using DMAP and EDCI, which is mild in reactivity, covers a diverse range of carboxylic acid acylating agents, is compatible with electron releasing and withdrawing substituents on the 1,3-indandione partner, and performs well in a polar aprotic solvent (for solubility reasons) This method cleanly afforded twenty five different products in yields of 32–96%.

Full text of DOI:10.1016/j.tet.2018.04.041

Accepted Manuscript
A method for C2 acylation of 1,3-indandiones
Brian J. Larsen, Robert J. Rosano, Thomas A. Ford-Hutchinson, Allen B. Reitz, Jay E.
Wrobel
PII:
S0040-4020(18)30430-7
10.1016/j.tet.2018.04.041
TET 29456
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 February 2018
Revised Date: 10 April 2018
Accepted Date: 15 April 2018
Please cite this article as: Larsen BJ, Rosano RJ, Ford-Hutchinson TA, Reitz AB, Wrobel JE, A method
for C2 acylation of 1,3-indandiones, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.041.
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ACCEPTED MANUSCRIPT
A Method for C2 Acylation of 1,3-Indandiones
Brian J. Larsen,a Robert J. Rosano,a Thomas A. Ford-Hutchinson,b Allen B. Reitzb, Jay E. Wrobelb*
Fox Chase Chemical Diversity Center, Inc.
a 3700 Horizon Drive, King of Prussia, PA 19406, USA
b 3805 Old Easton Road, Doylestown, PA 18902, USA
* Corresponding author: jwrobel@fc-cdci.com
Abstract:
The 1,3-indandione scaffold is an important structural motif used in the preparation of a large number of
industrial chemical and pharmaceutical compounds. However, few approaches allow for the direct C2 acylation
on these building blocks. A method was developed using DMAP and EDCI, which is mild in reactivity, covers
a diverse range of carboxylic acid acylating agents, is compatible with electron releasing and withdrawing
substituents on the 1,3-indandione partner, and performs well in a polar aprotic solvent (for solubility reasons)
This method cleanly afforded twenty five different products in yields of 32-96%.
O
4
O
4
DMAP (3.0 eq)
EDCI (3.0 eq)
5
OH
R'
O
5
R
+
R
HO
R'
DMF (anhydrous, 0.055M)
RT over 12-72 h
O
O
2-Acyl-1,3-Indandiones
Yields of 32-96%
1,3-Indandiones
Carboxylic Acids
(0.5 mmol scale)
(3.0 eq)
R' = alkyl, aralkyl, hetero-substituted alkyl, heteroaryl
R = H, 5-Br, 4-NO2, 5-Me
1

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Introduction:
1,3-Indandiones are versatile building blocks that have been used in the preparation of a large number of
heterocyclic pharmaceutical and industrial chemicals.1 2-Acyl 1,3-indandiones are found in the anticoagulant
rodenticides valone and diphenadione, best known as “first generation”
vitamin K antagonists (Figure 1).2 We required compounds with the 2-acyl-
1,3-indandione moiety and sought a general synthesis via acylation of 1,3-
indandiones but learned that a paucity of reaction conditions were available to
us. Note that we draw the 2-acyl-1,3-indandione moiety as the enol form with
an exocyclic double bond. X-ray, NMR and computational studies support
this form over the tricarbonyl and endocyclic enol forms,3-5 and the form as
Figure 1: First-generation
vitamin K antagonists.
drawn is consistent with our own NMR data.
Several methods currently exist for the synthesis of 2-acyl-1,3-indandiones (II) from various starting
materials (Scheme 1). As mentioned above few methods are reported for the direct 2-acylation of 1,3-
indandiones (I), and those that exist are not general, have harsh conditions and result in poor yields (pathway
A). These include 1) reaction with p-nitrophenol esters as acylating agent,6 and 2) reaction with acid chlorides
and aluminum chloride.7 Since this acylation has been recognized as a common problem, other methods have
been developed that bypass an acylation procedure. An example is reaction of o-phthalate esters with methyl
ketones8,9 (pathway B), however conditions are rather harsh since they require high temperatures and strong
base. Alternatively reaction of phthalate anhydrides (pathway C) with methyl ketones in base9 or with simple
alkyl ketones in base9,10 gives inconsistent yields and is of limited substrate scope. A recent intramolecular
method uses a phenoxy formate as a carbon monoxide source in a palladium catalyzed carbonylation of an o-
iodophenyl
β
-diketone to construct II (pathway D).11 Since we sought to prepare a diverse range of acyl
moieties appended to a variety of 1,3-indandione containing starting materials, none of these methods were
easily adaptable for our purposes. Thus, we
decided to re-examine direct acylation using
alternative chemistry. We were heartened in
that there was a growing body of work on the
acylation of other cyclic β-dicarbonyl
systems. For instance several investigators
described acylation of these systems with
different carboxylic acids using dicyclohexyl-
carbodiimide (DCC) or 1-ethyl-(3-(3-
dimethylamino)propyl)-carbodiimide (EDCI)
Scheme 1. Various methods for preparing 2-acyl 1,3-indandiones
usually with
dimethylamino pyridine
2

ACCEPTED MANUSCRIPT
(DMAP). Ring systems included were meldrums acid12,13, pyrimidine-2,4,6-triones14, tetramic acids15 and 1,3-
cyclohexandiones.16,17 Other acylation methods on 1,3-cyclohexandiones employed samarium trichloride
(SmCl3) with an acid chloride,18 or cyanogen bromide with an aldehyde.19 We here describe a simple one-pot
C2 acylation of 1,3-indandiones using EDCI and DMAP that achieves yields up to 96%. As starting materials,
we explored commercially available 1,3-indandiones with and without electron withdrawing and releasing
substituents along with a variety of diverse carboxylic acid building blocks as the acylating agents (Table 1).
Results/Discussion:
There are several problems to overcome with any method using a 1,3-indandione analog (I): O-
acylation, over-acylation and self-condensation (primarily bindone formation, III in Scheme 1, and other more
complex self-condensation products).20 Since the acylation reaction would compete with self-condensation for
consumption of the 1,3-indandione starting material, excess acylating agent could minimize the self-
condensation route, while using stoichiometric amounts of acylating agent would impede over-acylation. With
this in mind we had to strike a balance between these competing factors in determining the number of
equivalents of acylating agent to use.
First a series of studies were conducted on the parent 1,3-indandione (R = H in I, Scheme 1) and using
benzoic acid, phenylacetic acid and 3-methylbutyric acid or their acid chloride derivatives in attempts to
directly functionalize C2. In the process we screened various reagents, solvents, temperatures, concentrations,
times, and ratios, monitoring by LCMS to best optimize the reactions. Initially, we tried SmCl3 to promote a
direct C2 functionalization of 1,3-indandiones using acyl chlorides.18 Only trace amounts of desired product (II)
was observed. The byproducts included O-acylation, over-acylation, and self-condensation to bindone (III). We
also attempted acylation methodology using acyl chlorides with other Lewis acids (AlCl3 or MgCl2) or with
bases such as K2CO3 and DMAP. All of these initial attempts resulted in incomplete conversion and/or
inseparable mixtures, with formation of bindone (III), over-acylation products and/or other undesirable,
unidentified byproducts.
While the use of DCC and DMAP in dichloromethane12-17 gave desired products as determined by
LCMS, the reaction mixtures were plagued by difficulties in purification (e.g. removal of DCC related urea
byproducts). The intended use of any method we developed would be applied to privileged scaffolds that we
knew would have low solubility in organic solvents and thus not easily amenable to using chromatographic
methods. Thus, our method needed to provide crude reaction mixtures that could be easily purified by
trituration, recrystallization or acid-base workup. In order to combat these issues, a switch to the water-soluble
coupling reagent EDCI·HCl, which has been widely utilized in the field of peptide coupling reactions in
combination with additives, such as hydroxybenzotriazole (HOBT·hydrate). Furthermore, we sought to perform
the reactions in polar aprotic solvents such as DMF to overcome any future reaction mixture solubility issues.
We first examined four conditions: either 1.5 equivalents of carboxylic acid, EDCI·HCl and DMAP, or
3

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Table 1. Compilation of acylation results.
3.0 equivalents of carboxylic acid,
O
4
O
O
4
DMAP (3.0 eq)
EDCI (3.0 eq)
O
5
5
OH
R'
EDCI·HCl and DMAP, both with and
without the corresponding equivalent
amount of HOBT·hydrate. The HOBT
did not show any benefit to reaction
composition or rates so it was excluded
in further evaluations. Both the 1.5 and
3.0 equivalent regimens gave the desired
C2 acylation product, however the 1.5
equivalent format let to greater amounts
of bindone (III) formation (5-10% as
opposed to 1-5% for the 3.0 equivalent
format). Therefore, all remaining
reactions proceeded with 3.0 equivalents
of coupling agents. Acylation products II
are reported in Table 1.
+
R
R
HO
R'
DMF (anhydrous, 0.055M)
RT over 12-72 h
IV
I
O
II
1,3-Indandione
(0.5 mmol scale)
Carboxylic Acids
2-Acyl-1,3-Indandiones
(3.0 eq)
Compound
II Entry
%
Purification
R
R'
Isolated
Yield
Comment
Method
Number
1
H
CH2CH(CH3)2
A
79
known (refs 21, 22 )
2
3
4
5
6
7
5-CH3
5-Br
4-NO2
H
CH2CH(CH3)2
CH2CH(CH3)2
B
C
C
A
A
A
57
93
93
70a
35a
75
CH2CH(CH3)2
CH2(cyclohexyl)
CH2(cyclopentyl)
CH2CH2CH(CH3)2
H
H
known (ref 23 )
8
H
CH(CH3)2
A
92
known (refs 11, 21)
no reaction
9
H
H
C(CH3)3
-
-
-
-
10
C(CH3)2Ph
no reaction
11
12
13
14
15
16
H
H
CF2Ph
-
-
no reaction
Ph
-
-
< 20% conversion
H
2-benzofuran
2-benzofuran
2-benzofuran
2-benzofuran
C
B
C
C
93
96
90
92
5-CH3
5-Br
4-NO2
Optimal conditions were found
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
H
5-CH3
5-Br
4-NO2
H
CH2Ph
CH2Ph
C
B
C
C
B
B
C
B
C
B
-
78
81
90
95
68
78a
89
95
85
83
-
known (refs 24, 25)
by adding 1,3-indandione (I) to a dilute,
room temperature, premixed solution of
3.0 eq of carboxylic acid, DMAP, and
EDCI in DMF (9 mL, 0.055M of 1,3-
indandione). These reactions conditions
were repeated on a variety of substrates
varying the R’ group on the acid
component to explore substrate scope of
the reactions (Table 1).
CH2Ph
CH2Ph
CH(CH3)Ph
CHPh2
H
known ( ref 26);
H
CH2OPh
5-CH3
H
CH2OPh
CH2SO2Me
CH2SO2(p -tolyl)
CH2NHPh
H
H
decomposition
decomposition
<30% conversion
H
CH2NHBoc
CH2(N-morpholine)
CH2(1-(1H )-pyrazole)
-
-
H
-
-
H
C
B
C
C
91
44
68
32
5-CH3 CH2(1-(1H )-pyrazole)
5-Br CH2(1-(1H )-pyrazole)
4-NO2 CH2(1-(1H )-pyrazole)
Reaction of sterically unhindered
alkyl carboxylic acids with a methylene
aAfter treatment by described method, compound further purified by chromatography
group adjacent to the carbonyl (IV, R’ = CH2R”, entries 1, 5-7) were generally unproblematic and gave good
yields. This was also true for phenyl acetic acid (entry 17) and acetic acids with α-hetero atom-based electron
withdrawing groups (R’ = CH2R”, where R” is OPh - entry 23, SO2Me - entry 25 and SO2(p-tolyl) - entry 26).
Compounds with two alkyl or phenyl moieties at the carboxylic acid α-carbon also behaved well (R’ =
CH(CH3)2 - entry 8, CH(CH3)Ph - entry 21, and CHPh2 – entry 22). However more sterically hindered
carboxylic acids that have a tertiary substituted α-carbon were not reactive under these conditions (entries 9-
4

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11). Benzoic acid (entry 12) was also problematic where less than 20% conversion (by LCMS) occurred with
several bi-products including bindone (III) and O-acylation observed. O-Acylation and poor reactivity is also a
common problem for aromatic and highly hindered carboxylic acids used as acylating agents on tetramic acids15
and cyclohexane 1,3 diones17 using similar conditions to those reported here. However, the heteroaromatic acid,
2-benzofuran carboxylic acid (entry 13) gave excellent results. Alternatively, when we tried using acetic acids
with basic amine moieties on the α-carbon, we observed either decomposition (entry 27) or sluggish product
formation by LCMS (entry 29). Boc-protected glycine (entry 28) also led only to decomposition products. In
contrast, the mildly basic pyrazol-1-yl-acetic acid (entry 30, pKa of conjugate acid = 2.4) did form the desired
product in good yield. Of note, is the preparation of valone and diphenadione (121,22 and 2226 in Table 1) using
this method. Also, the 1H and 13C NMR spectra of 8 were entirely consistent with the published spectra of same
compound synthesized by phenoxy formate palladium catalyzed carbonlyation of 1-(2-iodo-phenyl)-4-methyl-
pentane-1,3-dione (compound 3m in the reference).11
In order to examine the effect of electron releasing (EDG) or electron withdrawing (EWG) substituents
on the 1,3-indandione, we reacted substituted 1,3-indandiones containing a 5-methyl substituent (I, R = 5-CH3,
mild EDG), a 5-bromo substituent (I, R = 5-Br, EWG) and a 4-nitro substituent (R = 3-NO2, strong EWG). We
also picked a diverse set of carboxylic acids including 2-methyl butyric acid (entries 2-4), 2-benzofuran
carboxylic acid (entries 14-16), phenyl acetic acid (entries 18-20), and pyrazol-1-yl-acetic acid (entries 31-33).
Generally, the electron releasing or withdrawing groups did not affect the yield of the product. The isolated
yields for the pyrazole containing compounds (entries 30-33) tended to be lower because of their high water
solubility where a substantial amount dissolved in aqueous phases on triturations and extractions. Since these
compounds (2-4, 14-16, 18-20, 24, and 30-33) were substituted on the 1,3 indandione ring they often gave rise
to geometric isomers on the NMR time scale, which was particularly evident from the 13C spectra.
Through these studies we have shown that direct C2 acylation of various unsubstituted and substituted
1,3-indandiones has been successfully achieved in a single reaction step. The substrate scope was explored via
changes to the R’ groups on the acid moiety (IV) and with EDG and EWG groups on the 1,3-indandione
scaffold (I). Ultimately, we believe this chemical transformation could find wide applications for the rapid
synthesis of a variety of related 2-acyl-1,3-indandiones.
EXPERIMENTAL SECTION
General. All reagents used in chemical synthesis were purchased from Aldrich Chemical Co. (Milwaukee, WI),
Alfa Aesar (Ward Hill, MA), Thermo Fisher Scientific (Pittsburgh, PA), Enamine-BB or obtained from the
1
Pennsylvania Drug Discovery Institute (PDDI) and were used without further purification. H NMR spectra
were obtained on a Varian Mercury 300-MHz NMR spectrometer. Chemical shifts were reported in parts per
million (δ) using various solvents as internal standards (CDCl3, δ 7.26 ppm; DMSO-d6, δ 2.50 ppm; TMS, δ
5

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1
0.00 ppm). H NMR splitting patterns were designated as singlet (s), doublet (d), doublet of doublets (dd),
triplet (t), or quartet (q). Splitting patterns that could not be interpreted or easily visualized were recorded as
multiplet (m). Coupling constants were reported in Hertz (Hz). Low-resolution electrospray mass spectral data
(LCMS) were used to monitor reaction progress and were determined using a Waters Alliance 2695 HPLC/MS
(Waters Symmetry C18, 4.6×75 mm, 3.5 µm) with a 2996-diode array detector from 210 to 400 nm using
HPLC-grade acetonitrile (w/0.1% TFA) in HPLC-grade H2O (w/0.1% TFA) acquiring over 9.1 minutes (using
5% to 95% acetonitrile over 7 min, holding at 95% ACN until 8.60 min mark, then going to 5% ACN until the
9.30 min mark). High Resolution Mass spectra (HRMS) were obtained on a Bruker micrOTOF-Q II at the Mass
Spectrometry & Proteomics Facility at Notre Dame University.
General Experimental Procedure: In a 20 or 40 mL reaction vial equipped with magnetic stir bar and Teflon-
lined cap, a solution of the corresponding carboxylic acid (1.5 mmol, 3.0 eq) and DMAP (183.3 mg, 1.5 mmol,
3.0 eq) in anhydrous DMF (9.0 mL) was homogenized by stirring for 5-10 min. EDCI·HCl (287.6 mg, 1.5
mmol, 3.0 eq) was added, and the resulting mixture was homogenized by stirring for 5-10 min. The
corresponding 1,3-indandione (0.5 mmol, 1.0 eq) was added, and the resulting mixture was resealed and stirred
for 12-72 h, monitoring by LCMS. When complete, workup method A, B, or C was used to isolate the final
products.
Workup Method A: The reaction was worked up by diluting with EtOAc (75 mL) and moving into a
separatory funnel, then quenching with 2.0 N HCl (40 mL) and shaking vigorously. The separated organic layer
was washed with 2.0 N HCl (50 mL), the aqueous layer was back-extracted with EtOAc (50 mL), and the
combined organics were washed sequentially with 2.0 N HCl (50 mL) and D.I. H2O (50 mL). The final organic
phase was dried over MgSO4, filtered, and concentrated in vacuo.
Workup Method B: The crude reaction mixture was quenched with 1.0 N HCl (40 mL), and a solid precipitant
was filtered as the desired product. The sample was dried overnight in vacuo at 30 °C.
Workup Method C: Cold 2.0 N HCl (20 mL) was added to the solution, and the mixture was cooled in an ice
bath. The resulting precipitant was filtered, washed with cold 2.0 N HCl (15 mL), water (15 mL), and dried in
vacuo. The solid was treated with 1.0 N NaOH (10 mL), sonicated for 5-10 min until fully suspended into
solution, then treated with DCM (10 mL) and further mixed/sonicated for 5 min. The suspended precipitant was
filtered, washed with DCM (5 mL), and dried in vacuo. The compound was dissolved in 2N HCl (10 mL) and
extracted with DCM (10 mL). The sample was dried and concentrated overnight in vacuo.
2-(3-Methylbutanoyl)-1H-indene-1,3(2H)-dione (1).21,22 The title compound was prepared according to the
general experimental procedure using isovaleric acid (166 ꢀL, 1.5 mmol) and 1,3-indandione (73 mg, 0.5
6

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1
mmol). Product was isolated using workup method A as a brown solid (91 mg, 79%); H NMR (300 MHz,
CDCl3) δ 7.89 – 7.80 (m, 2H), 7.79 – 7.64 (m, 2H), 2.94 – 2.76 (m, 2H), 2.32 – 2.12 (m, 1H), 1.04 (d, J = 6.67
Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 197.3, 188.6, 187.2, 140.9, 138.2, 135.1, 134.2, 122.9, 122.6, 109.2,
40.9, 27.6, 22.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C14H15O3, 231.1016; found, 231.1024.
5-Methyl-2-(2-phenylacetyl)-1H-indene-1,3(2H)-dione (2). The title compound was prepared according to the
general experimental procedure using isovaleric acid (166 ꢀL, 1.5 mmol) and 5-methyl-2,3-dihydro-1H-indene-
1
1,3-dione (80 mg, 0.5 mmol). Product was isolated using workup method B as a pink solid (69 mg, 57%). H
NMR (300 MHz, CDCl3) δ 7.73 (d, J = 7.62 Hz, 1H), 7.63 (s, 1H), 7.51 (t, J = 8.20 Hz, 1H), 2.85 (d, J = 7.03
Hz, 2H), 2.51 (s, 3H), 2.21 (td, J = 6.96, 13.62 Hz, 1H), 1.03 (d, J = 6.44 Hz, 6H). 13C NMR (75 MHz, CDCl3)
δ 196.7, 188.0, 187.7, 187.7, 186.2, 146.1, 144.9, 144.9, 141.5, 138.9, 138.9, 136.4, 136.1, 135.3, 135.6, 134.8,
134.5, 134.3, 134.2, 123.7, 123.2, 123.1, 122.9, 122.7, 122.5, 122.5, 122.1, 109.4, 68.1, 51.8, 40.8, 27.2, 23.6,
22.6, 22.5, 22.5, 22.4, 22.3, 22.2, 21.6, 21.5. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C15H17O3,
245.1172; found, 245.1190.
5-Bromo-2-(3-methylbutanoyl)-1H-indene-1,3(2H)-dione (3). The title compound was prepared according to the
general experimental procedure using isovaleric acid (166 ꢀL, 1.5 mmol) and 5-bromo-2,3-dihydro-1H-indene-
1,3-dione (113 mg, 0.5 mmol). Product was isolated using workup method C as a light pink solid (142 mg,
93%); 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.86 – 7.77 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 2.84 (dd, J =
7.0, 1.1 Hz, 2H), 2.27 – 2.13 (m, 1H), 1.07 – 0.90 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 188.2, 138.8, 137.8,
137.6, 137.1, 126.3, 124.7, 124.1, 109.3, 41.4, 29.9, 27.7, 22.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C14H14BrO3, 309.0121; found, 309.0113.
2-(3-Methylbutanoyl)-4-nitro-1H-indene-1,3(2H)-dione (4). The title compound was prepared according to the
general experimental procedure using isovaleric acid (166 ꢀL, 1.5 mmol) and 4-nitro-2,3-dihydro-1H-indene-
1
1,3-dione (96 mg, 0.5 mmol). Product was isolated using workup method C as a pink solid (126 mg, 93%); H
NMR (300 MHz, CDCl3) δ 8.13 – 7.79 (m, 3H), 2.89 (dd, J = 7.90, 7.26 Hz, 2H), 2.23 (dp, J = 13.67, 6.83 Hz,
13
1H), 1.04 (dd, J = 6.67, 2.70 Hz, 6H). C NMR (75 MHz, CDCl3) δ 192.1, 187.3, 182.5, 146.0, 135.7, 134.5,
129.9, 129.1, 128.3, 127.8, 126.2, 108.1, 38.9, 29.9, 22.8. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C14H14NO5, 276.0866; found, 276.0875.
2-(2-Cyclohexylacetyl)-1H-indene-1,3(2H)-dione (5). The title compound was prepared according to the general
experimental procedure using cyclohexylacetic acid (213 mg, 1.5 mmol) and 1,3-indandione (73 mg, 0.5
mmol). Product was isolated using workup method A, followed by column chromatography on a silica gel
column using hexanes/ethyl acetate as the eluent to provide a yellow solid (95 mg, 70%). 1H NMR (300 MHz,
CDCl3) δ 7.88 – 7.80 (m, 2H), 7.78 – 7.66 (m, 2H), 2.87 (d, J = 7.13 Hz, 2H), 1.90 (ddp, J = 10.66, 6.93, 3.57
13
Hz, 1H), 1.82 – 1.59 (m, 4H), 1.43 – 1.00 (m, 6H). C NMR (75 MHz, CDCl3) δ 197.3, 188.7, 187.3, 140.9,
7

ACCEPTED MANUSCRIPT
138.2, 135.1, 134.2, 122.9, 122.6, 109.3, 39.8, 37.0, 33.2, 26.2. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C17H19O3, 271.1329; found, 271.1349.
2-(2-Cyclopentylacetyl)-1H-indene-1,3(2H)-dione (6). The title compound was prepared according to the
general experimental procedure using cyclopentylacetic acid (192 mg, 1.5 mmol) and 1,3-indandione (73 mg,
0.5 mmol). Product was isolated using workup method A, followed by column chromatography on a silica gel
column using hexanes/ethyl acetate as the eluent to provide a yellow solid (45 mg, 35%). 1H NMR (300 MHz,
CDCl3) δ 7.89 – 7.80 (m, 2H), 7.79 – 7.64 (m, 2H), 2.99 (d, J = 7.49 Hz, 2H), 2.32 (p, J = 7.80 Hz, 1H), 1.89 –
1.24 (m, 8H). 13C NMR (75 MHz, CDCl3) δ 197.5, 188.7, 187.5, 140.9, 138.3, 135.1, 134.2, 122.9, 122.6,
108.8, 38.2, 37.9, 32.6, 25.0. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C16H17O3, 257.1172; found,
257.1171.
2-(4-Methylpentanoyl)-1H-indene-1,3(2H)-dione (7).23 The title compound was prepared according to the
general experimental procedure using 4-methylvaleric acid (189 ꢀL, 1.5 mmol) and 1,3-indandione (73 mg, 0.5
1
mmol). Product was isolated using workup method A as a brown oil (91 mg, 75%); H NMR (300 MHz,
CDCl3) δ 7.89 – 7.79 (m, 2H), 7.71 (ddd, J = 6.99, 4.65, 1.60 Hz, 2H), 3.03 – 2.92 (m, 2H), 1.79 – 1.51 (m,
13
3H), 0.97 (d, J = 6.31 Hz, 6H). C NMR (75 MHz, CDCl3) δ 197.4, 188.6, 188.3, 140.8, 138.3, 135.1, 134.1,
122.8, 122.5, 108.4, 35.4, 30.6, 28.2, 22.4. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C15H17O3,
245.1172; found, 245.
2-Isobutyryl-1H-indene-1,3(2H)-dione (8).11,21 The title compound was prepared according to the general
experimental procedure using isobutyric acid (140 ꢀL, 1.5 mmol) and 1,3-indandione (73 mg, 0.5 mmol).
1
Product was isolated using workup method A as a brown solid (99 mg, 92%); H NMR (300 MHz, CDCl3) δ
13
7.87 – 7.80 (m, 2H), 7.76 – 7.65 (m, 2H), 3.90 (p, J = 6.87 Hz, 1H), 1.27 (d, J = 6.91 Hz, 6H). C NMR (75
MHz, CDCl3) δ 197.8, 192.3, 140.8, 138.2, 135.1, 134.1, 122.9, 122.5, 107.1, 30.7, 19.1. HRMS (ESI/Q-TOF)
m/z: [M + H]+ calcd for C13H13O3, 217.0859; found, 217.0853.
2-(Benzofuran-2-carbonyl)-1H-indene-1,3(2H)-dione (13). The title compound was prepared according to the
general experimental procedure using 2-benzofurancarboxylic acid (243 mg, 1.5 mmol) and 1,3-indandione (73
1
mg, 0.5 mmol). Product was isolated using workup method C as a bright yellow solid (133.6 mg, 93%); H
NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 7.84 – 7.57 (m, 6H), 7.51 – 7.45 (m, 1H), 7.34 – 7.26 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ 167.5, 156.6, 147.2, 134.6, 129.1, 128.1, 124.1, 124.0, 123.8, 122.7, 120.5, 112.4,
107.3, 29.8. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C18H11O4, 291.0652; found, 291.0672.
5-Methyl-2-(3-methylbutanoyl)-1H-indene-1,3(2H)-dione (14). The title compound was prepared according to
the general experimental procedure using 2-benzofurancarboxylic acid (243 mg, 1.5 mmol) and 5-methyl-2,3-
dihydro-1H-indene-1,3-dione (80 mg, 0.5 mmol). Product was isolated using workup method B as a tan solid
(146 mg, 96%). 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 7.81 (t, J = 4.31 Hz, 2H), 7.72 – 7.62 (m, 2H), 7.60
8

ACCEPTED MANUSCRIPT
– 7.49 (m, 2H), 7.40 – 7.31 (m, 1H), 2.55 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 166.7, 156.2, 146.9, 146.0,
135.1, 128.7, 127.8, 123.8, 123.5, 122.9, 122.4, 120.0, 112.1, 107.4, 34.5, 21.8. HRMS (ESI/Q-TOF) m/z: [M +
H]+ calcd for C19H13O4, 305.0808; found, 305.0814.
2-(Benzofuran-2-carbonyl)-5-bromo-1H-indene-1,3(2H)-dione (15). The title compound was prepared
according to the general experimental procedure using 2-benzofurancarboxylic acid (243 mg, 1.5 mmol) and 5-
bromo-2,3-dihydro-1H-indene-1,3-dione (113 mg, 0.5 mmol). Product was isolated using workup method C as
1
a brown solid (165.2 mg, 90%); H NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 7.98 (s, 1H), 7.82 (dd, J = 13.76,
8.17 Hz, 2H), 7.72 (d, J = 8.00 Hz, 1H), 7.64 (d, J = 8.24 Hz, 1H), 7.54 (dd, J = 8.38, 7.09 Hz, 1H), 7.42 – 7.30
(m, 1H). 13C NMR (75 MHz, CDCl3) δ 167.4, 156.2, 151.7, 146.4, 141.6, 139.0, 138.3, 137.8, 137.1, 130.5,
129.6, 127.6, 127.3, 126.2, 125.7, 124.1, 123.9, 121.5, 121.0, 116.1, 112.3, 107.6, 106.6, 102.9, 77.4, 77.0, 76.6,
73.9, 66.7, 50.2, 29.7, 26.9, 19.8. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C18H10BrO4, 368.9757; found,
368.9749. HRMS (ESI/Q-TOF) m/z: [M + Na]+ calcd for C18H10BrO4Na, 390.9576; found, 390.9560. HRMS
(ESI/Q-TOF) m/z: [M – H]- calcd for C18H8BrO4, 366.961144; found 366.960341.
2-(Benzofuran-2-carbonyl)-4-nitro-1H-indene-1,3(2H)-dione (16). The title compound was prepared according
to the general experimental procedure using 2-benzofurancarboxylic acid (243 mg, 1.5 mmol) and 4-nitro-2,3-
dihydro-1H-indene-1,3-dione (96 mg, 0.5 mmol). Product was isolated using workup method C as a lime-green
solid (153 mg, 92%); 1H NMR (300 MHz, CDCl3) δ 9.33 (s, 1H), 8.17 – 7.84 (m, 3H), 7.80 (d, J = 8.0 Hz, 1H),
13
7.69 – 7.61 (m, 1H), 7.60 – 7.50 (m, 1H), 7.36 ppm (t, J = 7.4 Hz, 1H). C NMR (75 MHz, CDCl3) δ 196.1,
193.9, 169.1, 156.6, 141.6, 139.4, 136.2, 135.2, 130.3, 128.8, 128.3, 127.7, 126.5, 125.5, 124.6, 124.2, 123.4,
122.8, 121.2, 112.5, 106.1, 29.8. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C18H10NO6, 336.0503; found,
336.0516.
2-(2-Phenylacetyl)-1H-indene-1,3(2H)-dione (17).24,25 The title compound was prepared according to the
general experimental procedure using phenylacetic acid (204 mg, 1.5 mmol) and 1,3-indandione (73 mg, 0.5
1
mmol). Product was isolated using workup method C as a reddish-brown solid (102 mg, 78%); H NMR (300
MHz, DMSO-d6) δ 8.78 (t, J = 5.93 Hz, 1H), 7.84 (dd, J = 7.43, 1.53 Hz, 1H), 7.60 (d, J = 1.45 Hz, 1H), 7.50
(d, J = 7.45 Hz, 1H), 4.10 (q, J = 7.11 Hz, 2H), 4.02 (d, J = 5.89 Hz, 2H), 1.20 (t, J = 7.11 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 197.3, 188.3, 183.7, 140.8, 138.2, 135.1, 134.8, 134.2, 129.6, 128.8, 127.4, 122.9, 122.5,
108.2, 77.5, 77.0, 76.6, 38.1. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C17H13O3, 265.0859; found,
265.0861.
2-(Benzofuran-2-carbonyl)-5-methyl-1H-indene-1,3(2H)-dione (18). The title compound was prepared
according to the general experimental procedure using phenylacetic acid (204 mg, 1.5 mmol) and 5-methyl-2,3-
dihydro-1H-indene-1,3-dione (80 mg, 0.5 mmol). Product was isolated using workup method B as a tan solid
1
(113 mg, 81%). H NMR (300 MHz, CDCl3) δ 7.80 – 7.62 (m, 2H), 7.53 (dd, J = 7.91, 11.42 Hz, 1H), 7.46 –
9

ACCEPTED MANUSCRIPT
7.41 (m, 2H), 7.36 – 7.27 (m, 3H), 4.27 (s, 2H), 2.52 (d, J = 4.10 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 196.8,
196.7, 188.1, 188.1, 188.0, 183.1, 146.4, 146.4, 146.3, 145.3, 145.2, 141.5, 138.9, 138.9, 138.8, 136.2, 136.1,
136.0, 135.7, 135.6, 135.0, 134.9, 134.8, 134.7, 130.2, 129.5, 129.4, 128.5, 128.3, 128.0, 127.1, 126.9, 123.3,
123.2, 123.1, 123.0, 122.9, 122.7, 122.5, 122.7, 122.3, 108.7, 78.2, 78.1, 77.7, 77.7, 77.6, 49.0, 38.2, 38.1, 21.9,
21.7. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C18H15O3, 279.1016; found, 279.1020.
5-Bromo-2-(2-phenylacetyl)-1H-indene-1,3(2H)-dione (19). The title compound was prepared according to the
general experimental procedure using phenylacetic acid (204 mg, 1.5 mmol) and 5-bromo-2,3-dihydro-1H-
indene-1,3-dione (113 mg, 0.5 mmol). Product was isolated using workup method C as an orange solid (155
mg, 90%); 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 15.35 Hz, 1H), 7.91 – 7.78 (m, 1H), 7.78 – 7.65 (m, 1H),
7.46 – 7.37 (m, 2H), 7.37 – 7.26 (m, 3H), 4.26 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 186.7, 179.0, 176.5,
175.3, 163.8, 121.2, 120.4, 107.8, 51.7, 46.4. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C17H12BrO3,
342.9964; found, 342.9975.
4-Nitro-2-(2-phenylacetyl)-1H-indene-1,3(2H)-dione (20). The title compound was prepared according to the
general experimental procedure using phenylacetic acid (204 mg, 1.5 mmol) and 4-nitro-2,3-dihydro-1H-
indene-1,3-dione (96 mg, 0.5 mmol). Product was isolated using workup method C as an orange solid (145 mg,
1
95%); H NMR (300 MHz, CDCl3) δ 8.14 – 7.82 (m, 3H), 7.48 – 7.26 (m, 5H), 4.28 ppm (d, J = 6.4 Hz, 2H).
13C NMR (75 MHz, CDCl3) δ 194.3, 192.1, 190.5, 185.5, 182.6, 142.4, 140.2, 135.7, 134.9, 131.4, 129.5, 128.5,
128.0, 126.2, 125.5, 108.8, 41.7, 27.8, 23.2, 22.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C17H12NO5,
310.0710; found, 310.0723.
2-(2-Phenylpropanoyl)-1H-indene-1,3(2H)-dione (21). The title compound was prepared according to the
general experimental procedure using 2-phenylpropanoic acid (225 mg, 1.5 mmol) and 1,3-indandione (73 mg,
1
0.5 mmol). Product was isolated using workup method B as an orangish-brown solid (103 mg, 68%). H NMR
(300 MHz, CDCl3) δ 7.90 – 7.63 (m, 4H), 7.55 – 7.46 (m, 2H), 7.36 – 7.27 (m, 3H), 5.18 (q, J = 7.14 Hz, 1H),
1.63 (d, J = 7.17 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 197.8, 188.4, 187.9, 140.9, 140.5, 138.2, 135.2, 134.2,
128.8, 128.3, 127.6, 123.0, 122.6, 107.6, 40.8, 17.4. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C18H15O3,
279.1016; found, 279.1018.
2-(2,2-Diphenylacetyl)-1H-indene-1,3(2H)-dione (22).26 The title compound was prepared according to the
general experimental procedure using diphenylacetic acid (318 mg, 1.5 mmol) and 1,3-indandione (73 mg, 0.5
mmol). Product was isolated using workup method B, followed by column chromatography on a silica gel
1
column using dichloromethane as the eluent to provide a reddish-tan solid (133.1 mg, 78%). H NMR (300
MHz, CDCl3) δ 7.91 – 7.80 (m, 2H), 7.80 – 7.64 (m, 2H), 7.48 – 7.39 (m, 4H), 7.39 – 7.27 (m, 6H), 6.55 (s,
1H). 13C NMR (75 MHz, CDCl3) δ 197.7, 188.2, 184.8, 140.9, 138.4, 138.2, 135.4, 134.4, 129.4, 128.8, 127.7,
123.1, 122.7, 108.8, 51.9. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C23H17O3, 341.1172; found, 341.1184.
10

ACCEPTED MANUSCRIPT
2-(2-Phenoxyacetyl)-1H-indene-1,3(2H)-dione (23). The title compound was prepared according to the general
experimental procedure using phenoxyacetic acid (228 mg, 1.5 mmol) and 1,3-indandione (73 mg, 0.5 mmol).
1
Product was isolated using workup method C as a tan solid (124.6 mg, 89%). H NMR (300 MHz, CDCl3): δ
8.11 – 7.51 (m, 4H), 7.45 – 7.17 (m, 2H), 7.14 – 6.84 (m, 3H), 5.41 (s, 2H). 13C NMR (75 MHz, CDCl3): δ
196.5, 187.9, 180.4, 158.8, 141.1, 139.1, 135.4, 134.5, 129.8, 123.3, 122.9, 122.2, 115.7, 109.0, 65.1. HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C17H13O4, 281.0797; found, 281.0808.
5-Methyl-2-(2-phenoxyacetyl)-1H-indene-1,3(2H)-dione (24). The title compound was prepared according to
the general experimental procedure using phenoxyacetic acid (228 mg, 1.5 mmol) and 5-methyl-2,3-dihydro-
1H-indene-1,3-dione (80 mg, 0.5 mmol). Product was isolated using workup method B as a pink solid (139 mg,
1
95%). H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 7.62 Hz, 1H), 7.69 (s, 1H), 7.61 – 7.55 (m, 3H), 6.34 (t, J =
2.98 Hz, 1H), 5.62 – 5.61 (m, 2H), 2.53 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 179.1, 166.1, 158.4, 156.9,
146.3, 146.3, 146.3, 146.2, 146.1, 140.7, 135.9, 135.8, 135.7, 135.6, 135.4, 135.4, 135.2, 135.2, 135.1, 134.6,
131.0, 129.8, 129.6, 129.4, 129.4, 129.3, 129.2, 125.9, 123.6, 123.1, 123.0, 123.1, 122.7, 121.9, 121.9, 121.8,
121.6, 121.4, 121.1, 116.9, 115.6, 115.4, 115.2, 115.1, 114.9, 108.9, 71.8, 65.8, 65.4, 64.7, 64.5, 64.4, 21.8.
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C18H15O4, 295.0965; found, 295.0974.
2-(2-(Methylsulfonyl)acetyl)-1H-indene-1,3(2H)-dione (25). The title compound was prepared according to the
general experimental procedure using methylsulfonylacetic acid (207 mg, 1.5 mmol) and 1,3-indandione (73
1
mg, 0.5 mmol). Product was isolated using workup method C as a yellow solid (113 mg, 85%). H NMR (300
MHz, CDCl3) δ 8.01 – 7.87 (m, 2H), 7.87 – 7.73 (m, 2H), 4.74 (s, 2H), 3.14 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 196.3, 187.5, 169.2, 141.1, 138.5, 136.1, 135.3, 123.7, 123.3, 111.4, 56.7, 42.9. HRMS (ESI/Q-TOF)
m/z: [M + H]+ calcd for C12H11O5S, 267.0322; found, 267.0329.
2-(2-Tosylacetyl)-1H-indene-1,3(2H)-dione (26). The title compound was prepared according to the general
experimental procedure using 4-toluenesulfonylacetic acid (321 mg, 1.5 mmol) and 1,3-indandione (73 mg, 0.5
1
mmol). Product was isolated using workup method B as a reddish-orange solid (142 mg, 83%). H NMR (300
MHz, CDCl3) δ 7.92 – 7.84 (m, 3H), 7.84 – 7.72 (m, 3H), 7.32 (dd, J = 8.60, 0.70 Hz, 2H), 4.81 (s, 2H), 2.39 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 196.2, 187.0, 169.5, 145.6, 141.0, 138.4, 136.1, 135.8, 135.0, 130.0, 129.9,
128.7, 128.7, 128.6, 123.4, 123.1, 111.5, 58.2, 21.8, 21.7. HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C18H15O5, 343.0635; found, 343.0632.
2-(2-(1H-Pyrazol-1-yl)acetyl)-1H-indene-1,3(2H)-dione (30). The title compound was prepared according to
the general experimental procedure using 1-pyrazoleacetic acid (189 mg, 1.5 mmol) and 1,3-indandione (73 mg,
1
0.5 mmol). Product was isolated using workup method C as a tan solid (116.5 mg, 91%); H NMR (300 MHz,
DMSO-d6) δ 7.81 (s, 1H), 7.61 – 7.52 (m, 5H), 6.34 (br s, 1H), 5.49 ppm (s, 2H).1 HRMS (ESI/Q-TOF) m/z:
[M + H]+ calcd for C14H11N2O3, 255.0764; found, 255.0772.
11

ACCEPTED MANUSCRIPT
2-(2-(1H-Pyrazol-1-yl)acetyl)-5-methyl-1H-indene-1,3(2H)-dione (31). The title compound was prepared
according to the general experimental procedure using 1-pyrazoleacetic acid (189 mg, 1.5 mmol) and 5-methyl-
2,3-dihydro-1H-indene-1,3-dione (80 mg, 0.5 mmol). Product was isolated using workup method B as a tan
solid (59.4 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 7.79 – 7.73 (m, 1H), 7.67 (t, J = 3.85 Hz, 1H), 7.57 – 7.52
13
(m, 1H), 7.33 – 7.28 (m, 2H), 7.03 – 6.89 (m, 3H), 5.39 (s, 2H), 2.52 (s, 3H). C NMR (75 MHz, CDCl3) δ
176.2, 146.4, 140.2, 135.5, 130.6, 123.2, 122.8, 109.1, 106.1, 50.7, 21.8. HRMS (ESI/Q-TOF) m/z: [M +
H]+ calcd for C15H13N2O3, 269.0921; found, 269.0928.
2-(2-(1H-Pyrazol-1-yl)acetyl)-5-bromo-1H-indene-1,3(2H)-dione (32). The title compound was prepared
according to the general experimental procedure using 1-pyrazoleacetic acid (189 mg, 1.5 mmol) and 5-bromo-
2,3-dihydro-1H-indene-1,3-dione (113 mg, 0.5 mmol). Product was isolated using workup method C as a purple
solid (102.2 mg, 68%); 1H NMR (300 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.73 – 7.58 (m, 2H), 7.50 (s, 1H), 7.36
(d, J = 7.7 Hz, 1H), 6.34 (s, 1H), 5.41 ppm (s, 2H).2 HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C14H10BrN2O3, 332.9869; found, 332.9896. Since this compound was not soluble at any practical concentration
in a variety of deuterated solvents we were unable to obtain a 13C NMR spectrum of this compound.
2-(2-(1H-Pyrazol-1-yl)acetyl)-4-nitro-1H-indene-1,3(2H)-dione (33). The title compound was prepared
according to the general experimental procedure using 1-pyrazoleacetic acid (189 mg, 1.5 mmol) and 4-nitro-
2,3-dihydro-1H-indene-1,3-dione (96 mg, 0.5 mmol). Product was isolated using workup method C as a purple
solid (48.8 mg, 32%); 1H NMR (300 MHz, DMSO-d6) δ 8.87 (d, J = 7.11 Hz, 1H), 8.01 – 7.35 (m, 6H), 6.66 (s,
1H). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C14H10N3O5, 300.0615; found, 300.0615. Since this
compound was not soluble at any practical concentration in a variety of deuterated solvents we were unable to
obtain a 13C NMR spectrum of this compound.
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Acknowledgements
We wish to thank the National Institute of Lung, Blood and Heart grant R42 HL12312602 for funding. We
thank Nonka Sevona at the Mass Spectrometry & Proteomics Facility at Notre Dame University for running our
HRMS samples.
13