Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors

Accepted Manuscript

Pulla Reddy Boggu, Jungsuk Cho, Youngsoo Kim, Sang-Hun Jung

PII:

S0223-5234(18)30364-7

10.1016/j.ejmech.2018.04.030

EJMECH 10379

DOI:

Reference:

To appear in: European Journal of Medicinal Chemistry

Received Date: 13 February 2018

Revised Date: 6 April 2018

Accepted Date: 14 April 2018

Please cite this article as: P.R. Boggu, J. Cho, Y. Kim, S.-H. Jung, Identification of novel 2-benzyl-1-

indanone analogs as interleukin-5 inhibitors, European Journal of Medicinal Chemistry (2018), doi:

10.1016/j.ejmech.2018.04.030.

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ACCEPTED MANUSCRIPT

Graphical abstract:

Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors

ACCEPTED MANUSCRIPT

Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors

Pulla Reddy Boggu^a, Jungsuk Cho^a, Youngsoo Kim^b, Sang-Hun Jung^a*

^aCollege of Pharmacy and Institute of Drug Research and Development, Chungnam

National University, Daejeon 34134, Republic of Korea.

^bCollege of Pharmacy, Chungbuk National University, Cheongju 19421, Republic of Korea.

Abstract

A novel series of 2-benzyl-1-indanone analogs were investigated as IL-5 inhibitory activity.

Among the synthesized compounds, 7-(cyclohexylmethoxy)-2-(4-hydroxybenzyl)-2,3-

dihydro-1H-inden-1-one (7s, 100.0% inhibition at 30 µM, IC₅₀= 4.0 µM), and 7-

(cyclohexylmethoxy)-2-(3-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7t, 95.0% inhibition

at 30 µM, IC₅₀= 6.0 µM) showed the best inhibitory activity against IL-5. The 2-benzyl-1-

indanone analogs showed moderate to strong IL-5 inhibitory activity. Especially, hydroxyl

(HBD/HBA) substituent at position 3 or 4 on phenyl ring B showed potent IL-5 inhibition.

Additionally, the bulky hydrophobic cyclohexylmethoxy group at position 7 of the 1-

indanone ring is favorable for the inhibitory activity.

Key words: 1-Indanone analogs; interleukin-5; inhibitor; SAR.

*Corresponding author: jungshh@cnu.ac.kr

Present address: College of Pharmacy and Institute of Drug Research and Development,

Chungnam National University, Daejeon 34134, Republic of Korea.

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1. Introduction

Eosinophils can control local immune and inflammatory responses, and their accumulation in

blood and tissue is seriously related to several inflammatory and infectious diseases [1,2].

The development of eosinophil is being regulated mainly by the three cytokines such as

interleukin (IL)-5 and granulocyte macrophage colony stimulating factor (GM-CSF), and IL-

3 [2]. The most eosinophil-specific of these cytokines is IL-5, which has a critical role in the

differentiation, migration, activation, and survival of eosinophils [3–5]. In addition, IL-5

stimulates the release of eosinophils from the bone marrow into the peripheral circulation [6].

The key function of IL-5 in the production of eosinophils is best demonstrated by genetic

manipulation of mice [7,8]. Overproduction of IL-5 in transgenic mice outcomes in severe

eosinophilia and deletion of the IL-5 gene causes a noticeable reduction of eosinophils in

blood and lungs after allergen challenge [7,8]. Several clinical trials with humanized anti-IL-

5 antibody demonstrated the crucial function of IL-5 in regulating eosinophils in human.

These antibodies can diminish blood and bronchoalveolar eosinophilia caused by allergic

challenges or chronic diseases [9–11].

Hence, IL-5 produced by the activated Th2 lymphocytes plays a critical role in allergic

disease [12,13]. The specificity of IL-5 toward eosinophils makes a perfect target for

reducing these responses without profound interference with the overall immune system

compared to traditional immunosuppressive agents like glucocorticoids [14]. In this regard,

IL-5 antagonist monoclonal antibodies have been developed [15–17]. However, these have

serious immunogenicity problems as well as an economic burden. Thus, IL-5 antagonist with

a small molecular weight has been investigated. The small organic isothiazolone derivatives

were identified as the IL-5 antagonist through modification of Cys 66 in IL-5Rα [18]. Our

screening effort with natural products resulted in the discovery of sophoricoside (SOP, 1) and

its analogs [19] isolated from Sophora japonica as a novel inhibitors of IL-5 bioactivity with

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differential inhibition of IL-3 and GM-CSF bioactivities [20]. However, SOP (1) is

chemically and metabolically unstable glycoside and consequently the formation of stable

analogs as a candidate was inevitable. Therefore, structural requirements of this isoflavonone

for its inhibitory activity against IL-5 were investigated (1 and 2, Fig. 1) [21,22]. The

necessary structural characteristics of these isoflavonone analogs comprise a planar chromen-

4-one ring, the existence of hydrogen bonding donor (HBD) at 4-position of B ring, and the

introduction of hydrophobic groups at position 5, which might adjust permeability of these

isoflavones. However, the glycopyranosyl moiety of SOP is not needed for the activity

[21,22]. To further confirm the importance of ring B, a series of novel 3-benzylchromen-4-

ones (3) [23,24], hydroxyethylaminomethylchromen-4-one (4) [25,26] and 3-alkoxychromen-

4-one (5) analogs [27] were explored as IL-5 inhibitors. Our efforts have mainly focused to

identify the important moieties on chromen-4-one ring A and phenyl ring B. However, these

efforts toward a drug candidate with these analogs has not been fruitful due to their moderate

potency. Therefore, we decide to change its core structure to discover the more potent IL-5

inhibitors. Thus, 1-indanone scaffold was considered as a rational bioisosteric replacement of

chromen-4-one ring. Accordingly, a series of novel 2-benzylidene-1-indanone 6 and 2-

benzyl-1-indanone 7 derivatives (Fig. 2) was synthesized and evaluated their inhibitory

activity against IL-5.

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Fig. 1. Reported natural and synthetic IL-5 inhibitors

Fig. 2. Design of novel 1-indanone scaffold 6 and 7 as IL-5 inhibitor.

2. Chemistry

Scheme 1 represents the synthesis of novel 2-benzylidene-1-indanone 6 and 2-benzyl-1-

indanone 7 compounds, which structure is described in Table 1. The phenol (8) was reacted

with 3-chloropropanoyl chloride in the presence of anhydrous AlCl₃at 120 °C to give 7-

hydroxy-1-indanone (9) [28], which is further reacted with appropriate alkyl or benzyl halide

in the presence of K₂CO₃in DMF at 60 °C condition [29] to obtain the intermediate

compounds 10a [30], 10b, and 10c. 2-Benzylidene-1-indanones 6a-j were synthesized by

aldol condensation of the corresponding alkylated 1-indanone compound (10a-c) with an

appropriate aldehyde in the presence of 10% aqueous NaOH solution. Compounds 6k and 6l

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were prepared from the methoxymethoxy (MOM) group protected compounds 6i and 6j by

reaction with conc. HCl with high yields, respectively. The preparation of substituted 2-

benzylidene-7-hydroxy-1-indanones 6m-o was achieved from the corresponding compounds

6a-c by deprotection of PMB group with trifluoroacetic acid (TFA). Subsequently, 6n was

alkylated with (bromomethyl)cyclohexane using K₂CO₃as a base to give final compound 6p.

Scheme 1. Synthesis of 2-benzylidene-1-indanone and 2-benzyl-1-indanone derivatives 6a-p

and 7a-z (substituents are denoted in Table 1). Reagents and Conditions: (a) i)

Cl(CH₂)₂COCl, 80 °C, 2 h; ii) AlCl₃, rt - 120 °C, 5 h, 41%; (b) R¹-Br/Cl, K₂CO₃, DMF, 60

°C, 3 h, 75 - 91%; (c) R²-Ph-CHO, 10% aq.NaOH, EtOH, rt, 3 - 12 h, 65 - 91%; (d) Conc.

HCl, MeOH, 60 °C, 3 h, 50 – 85%; (e) TFA, DCM, 0 °C to rt 2 h, 65 – 70%; (f) CyCH₂Br,

K₂CO₃, acetone, reflux, 5 h, 45%; (g) 10% Pd-C, H₂, MeOH:EtOAc (1:1), rt, 2 h, 60 - 78%;

(h) R¹-Br, K₂CO₃, DMF, 60 °C, 3 h, 55 - 69%.

To prepare the 2-benzyl-7-hydroxy-1-indanones 7a-g, the corresponding p-methoxybenzyl

(PMB) protected indanones 6a, 6b, 6d-h were reacted with hydrogen gas in the presence of

10% Pd-C in methanol to give 7a-g. The obtained 1-indanone compounds 7b-g were further

alkylated with appropriate halide to get final 2-benzyl-7-alkoxy-1-indanones 7h-r. The

phenolic hydroxyl compounds 7s-z were successively obtained from the corresponding MOM

protected analogs (7k-r) by deprotection with conc. HCl in methanol.

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Table 1. Substituents and their IC₅₀values of synthesized 1-indanone compounds.

Substituents

IL-5

% Inhibition

at 30 µM ^b

0.0

^aCLog P

Comp. No.

^bIC₅₀

(µM)

>30.0

ND

R¹

R²

PMB ^c

PMB

PNB ^f

CH₂Cy^g

PNB

CH₂Cy

H

4-OH

4-OCH₃

H

4.839

5.425

5.506

6.219

6.005

4.931

4.755

5.895

4.663

5.802

3.266

3.852

3.933

6.388

3.320

3.905

4.699

4.485

3.412

6a

6b

6c

6d

6e

6f

6.0

5.0

4-Cl

29.0

4-CH₃

17.0

4-OMOM ^d

3-OMOM

2-OMOM

4-OMOM

4-OH

ND ^e

ND

6g

6h

6i

ND

23.5

>30.0

ND

6j

32.0

6k

6l

4-OH

47.0

4-OH

35.0

6m

6n

6o

6p

7a

7b

7c

7d

7e

H

4-OCH₃

H

25.0

H

40.0

CH₂Cy

H

4-OCH₃

4-OH

5.6

30.0

H

4-OCH₃

4-Cl

ND

H

ND

H

4-CH₃

ND

H

4-OMOM

ND

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H

3-OMOM

2-OMOM

4-OCH₃

4-Cl

3.412

5.806

7.236

7.022

5.949

6.477

5.066

5.395

5.856

5.806

6.385

4.974

5.303

5.253

ND

7f

H

7g

CH₂Cy

(CH₂)₂Cy

CH₂Ph ^h

(CH₂)₂Ph

CH₂Cy

(CH₂)₂Cy

CH₂Ph

44.0

70.0

68.0

90.0

ND

>30.0

20.5

24.5

17.0

ND

7h

7i

4-CH₃

7j

4-OMOM

3-OMOM

2-OMOM

4-OMOM

3-OMOM

2-OMOM

4-OH

7k

7l

ND

7m

ND

7n

ND

7o

ND

7p

ND

7q

ND

7r

100.0

95.0

13.0

78.0

70.0

59.0

60.5

47.0

96.0

70.2^h

4.0

7s

3-OH

6.0

7t

2-OH

>30.0

18.0

21.0

26.0

28.0

>30.0

5.0

7u

4-OH

7v

4-OH

7w

(CH₂)₂Ph

4-OH

7x

3-OH

7y

2-OH

7z

2

26.2

Budesonide

a

CLog P values are calculated by Chemdraw^®(ver. 11); ^b% Inhibition and IC₅₀values are

c

d

taken as a mean from three independent experiments; PMB = p-methoxybenzyl; MOM =

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e

f

g

h

methoxymethyl; ND = not detected; PNB = p-nitrobenzyl; Cy = cyclohexyl; Ph =

phenyl. ^hInhibition at 50 µM.

3. Conformational analysis and alignment studies

For finding the isostere of chromen-4-one of 2, 1-indanone moiety was selected for the

replacement since it has similar characteristics regarding hydrogen bonding capability and

shape. Thus, the conformational analysis and alignment studies (Fig. 3) were conducted.

Molecular models of chromen-4-one 2, 2-benzylidene-1-indanone 6l and 2-benzy-1-indanone

7s were constructed using SYBYL^®-x2.0 program package (Tripos Associates Inc.) [31] and

their geometry was optimized (Powell conjugate gradient minimization, termination at a

gradient of 0.0005 kcal/mol) [32] using the Tripos standard force field and Gasteiger-Huckel

atomic partial charges. All the molecules were aligned by an atom-by-atom least-square fit

and used the cyclohexylmethoxyphenyl structure as a template as represented. The 3D

structures of the analyzed compounds were assumed to be a bioactive conformation and were

aligned according to a cyclohexymethoxyphenyl template as shown in Fig. 3. The selected

dihedral angles and atomic distances are listed in Table 2 and 3 respectively.

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Fig. 3. Alignment studies of 2 (Green color), 7s (Cyan color), and 6l (Yellow color); (A)

Alignment of 2 and 7s; (B) Alignment of 2 and 6l; (C) Alignment of 7s and 6l.

Table 2. Torsion angle (°) and total energy (kcal/mol) of 2, 6l, and 7s.

Compound 2 ^a

Compound 6l ^a

Compound 7s ^a

(6.181 kcal/mol)

(18.256 kcal/mol)

(11.689 kcal/mol)

∠O₇-C₄-C₃-O₈

∠C₄-C₃-O₈-C₉

∠O₇-C₄-C₃-O₈

∠C₄-C₃-O₈-C₉

∠O₇-C₄-C₃-O₈

∠C₄-C₃-O₈-C₉

0.2

356.2

180.2

279.1

55.3

108.9

^aNumbers on the atoms of 2, 6l, and 7s are presented in Fig. 3.

Table 3. Distance (Å) in 2, 6l and 7s.

Compound 2 ^a

Compound 6l ^a

Compound 7s ^a

O₆-O₁₀9.348 O₆-O₁₀10.995 O₆-O₁₀7.162

O₇-O₁₀7.408 O₇-O₁₀

O₁-O₁₀7.378

8.652

-

O₇-O₁₀5.264

-

^aNumbers on the atoms of 2, 6l, and 7s are presented in Fig. 3; '-' Not applicable.

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4. Pharmacology

The inhibitory activity of 1-indanone analogs against IL-5 was evaluated using the IL-5

dependent pro-B Y16 cell line according to the previously reported procedure [19,27]. These

cells were incubated with 3 units/mL mIL-5 for 48 h in the presence or absence of the

sample, and then cell metabolism was measured as an index of proliferation, using 2-(4-

iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulphophenyl)-2H-tetrazolium sodium salt (WST-1).

The results of biological screening of 1-indanone analogs against IL-5 are listed in Table 1 as

% inhibition at 30 µM and IC₅₀values. The comprehensive assay protocols are described in

the experimental section.

5. Results and discussion

Initially, the IL-5 inhibitory activities of 2-benzylidene-1-indanone analogs 6 were tested and

these showed poor activity although their activities do not show considerable variations along

with the substituents on A and B rings of 6 (Table 1). The poor activity of 2-benzylidene-1-

indanone analogs might attribute to their inactive conformation (Fig. 3B).

In the next set of experiments, we reduced the double bond of 2-benzylidene-1-indanone

analogs 6 to 2-benzyl-1-indanones 7, which obtain conformational freedom around 2-benzyl

moiety. Therefore, these moieties could be properly located for binding. The saturation of

double bond of benzylidene 6m resulted in benzyl analog 7a (30.0% inhibition at 30 µM,

IC₅₀= >30.0 µM), which did not improve the activity. However, double bond reduction of 6l

to benzyl analog 7s (100.0% inhibition at 30 µM, IC₅₀= 4.0 µM) dramatically increased the

activity compared to 6l and 7a and it showed the similar activity compared to 2 (96.0%

inhibition at 30 µM, IC₅₀= 5.0 µM). This outcome implies that the free rotation of benzyl

group at position 2 and the hydrophobic cyclohexylmethoxy group at position 7 of 1-

indanone of analog 7 are crucial for the IL-5 inhibitory activity.

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With these encouraging results, the importance of hydrogen bonding donor property on

phenyl ring B was investigated. Accordingly, the phenolic hydroxyl group in 7s was masked

with hydrophobic groups capable to be a mild hydrogen bond acceptor such as

methoxymethoxy analog 7k (90.0% inhibition at 30 µM, IC₅₀= 17.0 µM) and methoxy

analog 7h (44.0% inhibition at 30 µM, IC₅₀= >30.0 µM). Analog 7k showed less activity and

analog 7h dramatically reduces the IL-5 inhibitory activity. These results intimated that the

hydroxyl group (HBD) on phenyl ring is critical for the activity. Next, to investigate the

importance of hydrophobic substituents on phenyl ring B of 7s, chloro analog 7i (70.0%

inhibition at 30 µM, IC₅₀= 20.5 µM) and methyl analog 7j (68.0% inhibition at 30 µM, IC₅₀

= 24.5 µM) were prepared. Both of them showed the lowest activity compared to 7s, which

indicated that hydrophilic hydroxyl group on ring B is necessary for the activity.

The promising activity of 7s led us to shift our focus toward finding the suitable position for

the hydroxyl group on phenyl ring B since the position of the hydroxyl group on phenyl ring

in the isoflavone analogs plays an important role for the IL-5 inhibition as we reported earlier

studies [23]. The position of the hydroxyl group on phenyl ring was shifted to position 3 as

shown in analogs 7t and position 2 as shown in 7u. Analog 7t (95.0% inhibition at 30 µM,

IC₅₀= 6.0 µM) showed similar activity compared to 7s, and 7u (13.0% inhibition at 30 µM,

IC₅₀= >30.0 µM) did not show any activity. These results strongly suggested that the

hydroxyl group at position 3 or 4 of phenyl ring B should be suitable for the IL-5 inhibitory

activity.

Thereafter, to confirm the optimum length of the hydrophobic group on 1-indanone ring A of

7s, the chain length was increased as shown in 7v (78.0% inhibition at 30 µM, IC₅₀= 18.0

µM), which reduced the activity. To confirming the necessity of optimum bulkiness,

cyclohexylmehoxy group in 7s and 7v was replaced with the planar group as shown in

benzyloxy analog 7w (70.0% inhibition at 30 µM, IC₅₀= 21.0 µM) and phenethoxy analog 7x

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(59.0% inhibition at 30 µM, IC₅₀= 26.0 µM). These caused the decrement in the activity

compared to 7s and 7v. Next, the positional change of the 4-hydroxyl group on phenyl ring B

of phenethyl analog 7x was performed as shown in 7y (60.5% inhibition at 30 µM, IC₅₀=

28.0 µM) and 7z (47.0% inhibition at 30 µM, IC₅₀= >30.0 µM), which did not improve the

inhibitory activity. These results obviously depicted that the bulkier cyclohexyl group than

phenyl and the position 4 of the hydroxyl group on phenyl ring B better contribute to the

activity.

In order to analyze the differences in the activity of inactive 6l and active 7s as IL-5 inhibitor,

we compared the 3D structural sketches of the chromen-4-one 2 and 1-indanone analogs 6l

and 7s (Fig. 3, Table 2 and 3) and observed a dramatic difference in the region benzylic

hydroxyl group at position 3 of chromen-4-one and at position 2 of 1-indanone analogs. As

∠

shown in Table 2, the dihedral angles ( C₄-C₃-C₈-C₉) of analog 2 is 108.9°, which indicates

that the benzyl group at position 3 of 2 is located out of the plane of the chromen-4-one ring.

∠

The corresponding dihedral angle ( C₄-C₃-C₈-C₉, Table 2) of 7s is 55.3°, which depicts that

the phenolic hydroxyl oxygen is located out of the plane of 1-indanone. Thus 2 and 7s have

∠

relatively similar conformation. However, the corresponding dihedral angle ( C₄-C₃-C₈-C₉=

180.2°, Table 2) of 6l indicated the rigid stretched conformation of 2-benzylidene-1-indanone

analogs unlike the conformations of 2 or 7s. Hence, this rigidity of 2-benzylidene-1-indanone

analogs markedly decreases the IL-5 inhibitory activity. Therefore, conformational study of

these analogs indicates that the folded conformation of 2-benzyl-1-indanone 7s could be

much closer to the effective conformation for binding to the putative receptor.

6. Conclusion

A novel series of 1-indanone analogs for the inhibitory effect in the IL-5 bioassay were

investigated. Among the synthesized compounds, 7s (100.0% inhibition at 30 µM, IC₅₀= 4.0

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µM), and 7t (95.0% inhibition at 30 µM, IC₅₀= 6.0 µM) showed the best inhibitory activity

against IL-5. On the basis of SAR (Fig. 4), the 2-benzyl-1-indanone analogs showed strong to

moderate activity. Especially, hydrophilic hydroxyl (HBD) substituent at position 3 or 4 on

phenyl ring B showed potent IL-5 inhibition. Additionally, the bulky hydrophobic

cyclohexylmethoxy substitution on 1-indanone ring is favorable for the inhibitory activity.

Altogether, we identified the new 2-benzyl-1-indanone scaffold as a lead from 2-benzyl-

chromen-4-one 2 compound for finding a novel potent IL-5 inhibitor.

Figure 4. SAR of the novel 1-indanone analogs.

7. Materials and methods

7.1. Chemistry

Melting points (mp) were determined on an Electro thermal 1A 9100 MK2 apparatus and are

uncorrected. All commercial chemicals were used as obtained and all solvents were purified

by distillation prior to use applying the standard procedures [33]. Thin layer chromatography

(TLC) was performed on E Merck silica gel GF-254 pre-coated plates, identification was

performed under UV illumination (λ = 254 nm), and colorization with Iodine and KMnO₄.

All compounds were purified by flash column chromatography which was performed on E

Merck silica gel (230–400 mesh). Infrared (IR) spectra were recorded on a Nicolet 380 model

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1

13

FTIR. H NMR and C NMR spectra were measured against the peak of tetramethylsilane

using a Bruker Fourier 300 NMR (300 MHz) and JEOL, JNM-AL400 NMR (400 MHz)

spectrometer. High resolution mass spectrum (HRMS) were measured in ESI ionization using

AB Sciex Triple TOF 5600 LCMS instrument.

7.1.1. General synthetic procedure for the preparation of compounds (6a-j)

To a solution of the corresponding 7-benzyloxy or alkoxy 1-indanone (10a-c, 2.05 mmol) and

appropriate benzaldehydes (4.09 mmol) in EtOH (10 mL), a 10% aq.NaOH solution (2.0 mL)

was added. The resulting solution was stirred at room temperature for 3 - 12 h. The off white

precipitated slurry was cooled in an ice bath, filtered, and washed with cold ethanol. The

collected solid was dried in vacuo to afford the title compounds 6a-j. In those reactions where

no precipitation occurred, the reaction solutions were extracted with ethyl acetate (EtOAc)

and washed with water and brine solution. The obtained crude products were further purified

by flash silica gel column chromatography.

7.1.1.1.

2-(4-Hydroxybenzylidene)-7-((4-methoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-one

(6a). This compound preparation was done by work up with water/EtOAc extraction

followed by flash silica gel (230 - 400 mesh) column chromatography (eluting with 0-15%

ethyl acetate in hexanes) to afford the title compound. Yield 65%; Yellow solid; mp = 217 –

1

219 °C; IR (neat) 3013, 2969, 1736, 1599, 1582, 1365, 1216, 1203, 1032, 954, 818 cm^-1; H

NMR (300 MHz, DMSO-d₆)

δ 7.54 - 7.64 (m, 3H), 7.45 (d, J = 8.47 Hz, 2H), 7.33 (br. s.,

1H), 7.16 (d, J = 7.45 Hz, 1H), 7.06 (d, J = 8.10 Hz, 1H), 6.96 (d, J = 8.47 Hz, 2H), 6.88 (d, J

= 8.38 Hz, 2H), 5.19 (s, 2H), 3.99 (br. s., 2H), 3.76 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆)

δ

191.1, 159.3, 159.1, 157.2, 152.2, 136.3, 132.8, 132.2, 131.9, 129.0, 128.9, 126.3, 126.1,

118.4, 116.1, 113.9, 111.6, 69.2, 55.2, 31.8; HRMS (ESI) calculated for C₂₄H₂₀O₄[M+H]⁺

373.1440, found 373.1461.

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7.1.1.2.

7-((4-Methoxybenzyl)oxy)-2-(4-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one

(6b). Yield 91%; Off white solid; mp = 202 – 205 °C; IR (neat) 3002, 2969, 1736, 1588,

1513, 1365, 1216, 1203, 1038, 948, 826 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ

7.58 - 7.65 (m,

3H), 7.45 - 7.52 (m, 3H), 7.09 (d, J = 7.45 Hz, 1H), 6.98 (d, J = 8.75 Hz, 2H), 6.93 (d, J =

8.66 Hz, 2H), 6.86 (d, J = 8.29 Hz, 1H), 5.26 (s, 2H), 3.98 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H);

¹³C NMR (100 MHz, CDCl₃)

δ 192.3, 160.6, 159.3, 157.8, 152.0, 135.8, 132.8, 132.5, 132.4,

128.8, 128.4, 128.3, 127.1, 118.2, 114.4, 114.0, 111.5, 70.0, 55.3, 55.2, 32.3; HRMS (ESI)

calculated for C₂₅H₂₂O₄[M+H]⁺387.1596, found 387.1619.

7.1.1.3. 2-Benzylidene-7-((4-methoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-one (6c). Yield

85%; White solid; mp = 161 – 163 °C; IR (neat) 2934, 1695, 1586, 1515, 1244, 1038, 955,

791 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 7.60 - 7.70 (m, 3H), 7.38 - 7.52 (m, 6H), 7.10 (d, J =

7.54 Hz, 1H), 6.93 (d, J = 8.66 Hz, 2H), 6.87 (d, J = 8.29 Hz, 1H), 5.26 (s, 2H), 3.98 - 4.06

(m, 2H), 3.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

δ

192.1, 159.3, 157.9, 152.1, 136.1,

135.7, 135.1, 132.7, 130.6, 129.4, 128.9, 128.7, 128.3, 126.9, 118.2, 114.0, 111.5, 70.0, 55.2,

32.2; HRMS (ESI) calculated for C₂₄H₂₀O₃[M+H]⁺357.1490, found 357.1514.

7.1.1.4.

2-(4-Chlorobenzylidene)-7-((4-methoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-one

(6d). Yield 81%; Off white solid; mp = 140 – 142 °C; IR (neat) 2905, 2838, 1695, 1593,

1

1512, 1234, 1062, 823, 768 cm^-1; H NMR (400 MHz, CDCl₃)

δ 7.54 - 7.61 (m, 3H), 7.45 -

7.52 (m, 3H), 7.43 (d, J = 8.54 Hz, 2H), 7.09 (d, J = 7.32 Hz, 1H), 6.93 (d, J = 8.54 Hz, 2H),

6.88 (d, J = 8.29 Hz, 1H), 5.26 (s, 2H), 3.98 (s, 2H), 3.82 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃)

δ 191.9, 159.3, 157.9, 151.9, 136.3, 135.6, 135.3, 134.1, 131.7, 131.2, 129.2, 128.6,

128.3, 126.7, 118.1, 114.0, 111.5, 69.9, 55.2, 32.1; HRMS (ESI) calculated for C₂₄H₁₉ClO₃

[M+H]⁺391.1101, found 391.1121.

ACCEPTED MANUSCRIPT

7.1.1.5. 7-((4-Methoxybenzyl)oxy)-2-(4-methylbenzylidene)-2,3-dihydro-1H-inden-1-one (6e).

Yield 77%; Off white solid; mp = 145 – 147 °C; IR (neat) 2965, 1694, 1599, 1511, 1242,

1067, 815 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 7.55 - 7.62 (m, 3H), 7.45 - 7.53 (m, 3H), 7.28

(br. s., 1H), 7.25 (br. s., 1H), 7.09 (d, J = 7.08 Hz, 1H), 6.93 (d, J = 8.75 Hz, 2H), 6.87 (d, J =

13

8.20 Hz, 1H), 5.26 (s, 2H), 4.01 (s, 2H), 3.82 (s, 3H), 2.41 (s, 3H); C NMR (100 MHz,

CDCl₃)

δ 192.3, 159.3, 157.8, 152.1, 139.8, 136.0, 134.1, 132.9, 132.7, 130.7, 129.7, 128.8,

128.3, 127.0, 118.2, 114.0, 111.4, 70.0, 55.2, 32.3, 21.4; HRMS (ESI) calculated for

C₂₅H₂₂O₃[M+H]⁺371.1647, found 371.1669.

7.1.1.6.

7-((4-Methoxybenzyl)oxy)-2-(4-(methoxymethoxy)benzylidene)-2,3-dihydro-1H-

inden-1-one (6f). Yield 79%; White solid; mp = 146 - 148 °C; IR (neat) 2929, 1737, 1703,

1588, 1503, 1366, 1234, 1172, 1038, 993, 822, 789, 771 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ

7.56 - 7.66 (m, 3H), 7.44 - 7.52 (m, 3H), 7.06 - 7.16 (m, 3H), 6.93 (d, J = 8.66 Hz, 2H), 6.87

(d, J = 8.20 Hz, 1H), 5.26 (s, 2H), 5.24 (s, 2H), 3.98 (s, 2H), 3.82 (s, 3H), 3.51 (s, 3H);

HRMS (ESI) calculated for C₂₆H₂₄O₅[M+H]⁺417.1702, found 417.1723.

7.1.1.7.

7-((4-Methoxybenzyl)oxy)-2-(3-(methoxymethoxy)benzylidene)-2,3-dihydro-1H-

inden-1-one (6g). Yield 76%; White solid; mp = 114 – 116 °C; IR (neat) 2950, 1737, 1703,

1

1588, 1478, 1224, 1034, 1014, 881, 791, 759 cm^-1; H NMR (300 MHz, CDCl₃)

δ 7.59 (s,

1H), 7.44 - 7.53 (m, 3H), 7.40 - 7.28 (m, 3H), 7.10 (d, J = 7.54 Hz, 2H), 6.93 (d, J = 8.66 Hz,

2H), 6.87 (d, J = 8.29 Hz, 1H), 5.25 (d, J = 7.08 Hz, 4H), 4.01 (s, 2H), 3.82 (s, 3H), 3.52 (s,

3H); HRMS (ESI) calculated for C₂₆H₂₄O₅[M+H]⁺417.1702, found 417.1723.

7.1.1.8.

7-((4-Methoxybenzyl)oxy)-2-(2-(methoxymethoxy)benzylidene)-2,3-dihydro-1H-

inden-1-one (6h). Yield 85%; White solid; mp = 127 – 128.5 °C; IR (neat) 2969, 2931, 1737,

1

1703, 1588, 1478, 1255, 1229, 1035, 1018, 993, 820, 790, 744 cm^-1; H NMR (300 MHz,

CDCl₃)

δ 8.10 (s, 1H), 7.68 (d, J = 7.54 Hz, 1H), 7.44 - 7.55 (m, 3H), 7.30 - 7.39 (m, 1H),

ACCEPTED MANUSCRIPT

7.21 (d, J = 8.29 Hz, 1H), 7.03 - 7.14 (m, 2H), 6.94 (d, J = 8.57 Hz, 2H), 6.88 (d, J = 8.29

Hz, 1H), 5.26 (d, J = 5.96 Hz, 4H), 3.98 (s, 2H), 3.82 (s, 3H), 3.51 (s, 3H); HRMS (ESI)

calculated for C₂₆H₂₄O₅[M+H]⁺417.1702, found 417.1723.

7.1.1.9. 2-(4-(Methoxymethoxy)benzylidene)-7-((4-nitrobenzyl)oxy)-2,3-dihydro-1H-inden-1-

one (6i). Yield 78%; Light yellow solid; mp = 180 – 182 °C; IR (neat) 3029, 2936, 1737,

1

1703, 1591, 1509, 1475, 1452, 1274, 1229, 1150, 1076, 996, 920, 772, 736, 694 cm^-1; H

NMR (300 MHz, CDCl₃)

δ 8.28 (d, J = 8.85 Hz, 2H), 7.81 (d, J = 8.85 Hz, 2H), 7.59 - 7.66

(m, 3H), 7.52 (t, J = 7.74 Hz, 1H), 7.10 - 7.19 (m, 3H), 6.84 (d, J = 8.10 Hz, 1H), 5.38 (s,

2H), 5.24 (s, 2H), 4.01 (s, 2H), 3.50 (s, 3H); HRMS (ESI) calculated for C₂₅H₂₁NO₆[M+H]⁺

432.1447, found 432.1469.

7.1.1.10. 7-(Cyclohexylmethoxy)-2-(4-(methoxymethoxy)benzylidene)-2,3-dihydro-1H-inden-

1-one (6j). Yield 72%; White solid; mp = 116 - 117 °C; IR (neat) 2922, 2852, 1738, 1599,

1

1366, 1233, 1060, 1001, 829, 790, 770 cm^-1; H NMR (300 MHz, CDCl₃)

δ 7.46 - 7.66 (m,

4H), 7.02 - 7.17 (m, 3H), 6.82 (d, J = 8.20 Hz, 1H), 5.24 (s, 2H), 3.97 (s, 2H), 3.92 (d, J =

6.05 Hz, 2H), 3.50 (s, 3H), 1.91 - 2.02 (m, 3H), 1.67 - 1.85 (m, 3H), 1.10 - 1.39 (m, 5H); ¹³C

NMR (100 MHz, CDCl₃)

δ 192.3, 158.6, 158.1, 151.9, 136.0, 133.4, 132.2, 132.0, 129.5,

126.6, 117.5, 116.5, 110.4, 94.2, 73.9, 56.1, 37.4, 32.2, 29.7, 26.4, 25.8; HRMS (ESI)

calculated for C₂₅H₂₈O₄[M+H]⁺393.2066, found 393.2089.

7.1.2. General synthetic procedure for the preparation of compounds (6k and 6l)

A solution of the corresponding MOM protected compound (6i or 6j; 0.51 mmol) and

Conc.HCl (0.2 mL) in MeOH was stirred at 60 °C for 3 h. The solution was concentrated

under vacuum, diluted with EtOAc and then washed with water. The organic layer was dried

over anhydrous Na₂SO₄, filtered and evaporated by vacuum. The residue was subjected to

ACCEPTED MANUSCRIPT

flash silica gel (230-400 mesh) column chromatography (eluting with 5 - 20% ethyl acetate in

hexanes) to afford the title compounds.

7.1.2.1. 2-(4-Hydroxybenzylidene)-7-((4-nitrobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (6k).

This compound was prepared from 6i. Yield 67%; Yellow solid; mp = 271 – 272 °C; IR

(neat) 3015, 2969, 2944, 1737, 1576, 1515, 1437, 1365, 1228, 1204, 1077, 826, 763 cm^-1; ¹H

NMR (400 MHz, DMSO-d₆)

δ 10.08 (br. s., 1H), 8.30 (d, J = 7.80 Hz, 2H), 7.85 (d, J = 7.56

Hz, 2H), 7.63 (d, J = 7.07 Hz, 3H), 7.38 (br. s., 1H), 7.21 (d, J = 6.34 Hz, 1H), 7.06 (d, J =

13

8.78 Hz, 1H), 6.90 (d, J = 7.56 Hz, 2H), 5.46 (br. s., 2H), 4.02 (br. s., 2H); C NMR (100

MHz, DMSO-d₆)

δ 191.1, 159.3, 156.6, 152.3, 147.1, 145.2, 136.3, 132.9, 132.1, 132.0,

127.7, 126.2, 126.1, 123.7, 118.9, 116.1, 111.3, 68.2, 31.8; HRMS (ESI) calculated for

C₂₃H₁₇NO₅[M+H]⁺388.1185, found 388.1206.

7.1.2.2. 7-(Cyclohexylmethoxy)-2-(4-hydroxybenzylidene)-2,3-dihydro-1H-inden-1-one (6l).

This compound was prepared from 6j. Yield 75%; Yellow solid; mp = 227 – 229 °C; IR

1

(neat) 3218, 2921, 2855, 1738, 1577, 1437, 1346, 1198, 1061, 830, 758 cm^-1; H NMR (300

MHz, DMSO-d₆) δ 10.05 (s, 1H), 7.53 - 7.62 (m, 3H), 7.30 (s, 1H), 7.13 (d, J = 7.45 Hz, 1H),

6.96 (d, J = 8.20 Hz, 1H), 6.89 (d, J = 8.57 Hz, 2H), 3.97 (s, 2H), 3.90 (d, J = 6.33 Hz, 2H),

13

1.61 - 1.94 (m, 6H), 1.03 - 1.35 (m, 5H); C NMR (100 MHz, DMSO-d₆) δ 190.9, 159.2,

157.8, 152.0, 136.2, 132.7, 132.2, 131.6, 126.3, 125.8, 117.9, 116.0, 110.7, 73.1, 37.0, 31.7,

29.0, 26.1, 25.3; HRMS (ESI) calculated for C₂₃H₂₄O₃[M+H]⁺349.1803, found 349.1824.

7.1.3. General synthetic procedure for the preparation of compounds (6m-o)

Trifluoroacetic acid (5 mL) was added to a solution of the corresponding p-

methoxybenzylated compound 6a-c (2.58 mmol) in dichloromethane (3 mL) at 0 °C. The

resulting solution was allowed to ambient temperature and stirred for 2 h. After completion of

the reaction, the mixture was concentrated in vacuo. The resulting material was dissolved in

ACCEPTED MANUSCRIPT

EtOAc and then washed with water, NaHCO₃solution, and brine solution. The organic layer

was dried over anhydrous Na₂SO₄, concentrated under reduced pressure which was subjected

to flash silica gel (230-400 mesh) column chromatography (eluting with 0 - 10% ethyl acetate

in hexanes) to afford the title compounds.

7.1.3.1. 7-Hydroxy-2-(4-hydroxybenzylidene)-2,3-dihydro-1H-inden-1-one (6m). This

compound was prepared from 6a. Yield 65%; Yellow solid; mp = 216 – 218 °C; IR (neat)

3400 – 3200, 3015, 2932, 1737, 1656, 1594, 1559, 1509, 1359, 1206, 1188, 1166, 1006, 959,

833, 791 cm^-1; ¹H NMR (300 MHz, DMSO-d₆)

δ 10.09 (s, 1H), 9.99 (s, 1H), 7.63 (d, J = 8.66

Hz, 2H), 7.48 (t, J = 7.78 Hz, 1H), 7.37 (s, 1H), 7.04 (d, J = 7.36 Hz, 1H), 6.89 (d, J = 8.66

13

Hz, 2H), 6.80 (d, J = 8.01 Hz, 1H), 3.98 (s, 2H); C NMR (100 MHz, DMSO-d₆)

δ 193.2,

159.4, 156.9, 150.9, 136.5, 133.0, 132.3, 131.9, 126.2, 124.1, 116.8, 116.1, 114.2, 31.9;

HRMS (ESI) calculated for C₁₆H₁₂O₃[M+H]⁺253.0864, found 253.0885.

7.1.3.2. 7-Hydroxy-2-(4-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one (6n). This

compound was prepared from 6b. Yield 68%; White solid; mp = 136 – 138 °C; IR (neat)

1

3299, 3003, 2835, 1737, 1671, 1594, 1514, 1365, 1173, 1034, 959, 826, 789, 772 cm^-1; H

NMR (300 MHz, DMSO-d₆)

δ 10.04 (s, 1H), 7.73 (d, J = 8.66 Hz, 2H), 7.49 (t, J = 7.78 Hz,

1H), 7.41 (s, 1H), 7.01 - 7.10 (m, 3H), 6.80 (d, J = 8.10 Hz, 1H), 4.00 (s, 2H), 3.83 (s, 3H);

¹³C NMR (100 MHz, DMSO-d₆)

δ

193.0, 160.6, 156.9, 151.0, 136.5, 133.0, 132.6, 131.6,

127.7, 124.0, 116.8, 114.6, 114.3, 55.4, 31.8; HRMS (ESI) calculated for C₁₇H₁₄O₃[M+H]⁺

267.1021, found 267.1044.

7.1.3.3. 2-Benzylidene-7-hydroxy-2,3-dihydro-1H-inden-1-one (6o). This compound was

prepared from 6c. Yield 70%; White solid; mp = 145 – 147 °C; IR (neat) 3311, 3027, 2927,

1674, 1625, 1610, 1468, 1357, 1295, 1177, 1044, 793, 751 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ

9.29 (s, 1H), 7.62 - 7.72 (m, 3H), 7.42 - 7.55 (m, 4H), 7.05 (d, J = 7.35 Hz, 1H), 6.85 (d, J

ACCEPTED MANUSCRIPT

= 8.20 Hz, 1H), 4.03 (s, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ 196.9, 158.2, 149.4, 137.5,

135.1, 134.5, 134.0, 130.8, 130.0, 129.1, 123.7, 116.9, 114.0, 32.4; HRMS (ESI) calculated

for C₁₆H₁₂O₂[M+H]⁺237.0915, found 237.0939.

7.1.4. 7-(Cyclohexylmethoxy)-2-(4-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one (6p)

To a solution of the 7-hydroxy-2-(4-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one (6n,

0.939 mmol) in acetone (10 mL), K₂CO₃(2.25 mmol) and (bromomethyl)cyclohexane (1.126

mmol) were added. The resulting solution was refluxed until complete conversion of the

starting material (5 h). After cooling to ambient temperature, the reaction mixture was

concentrated under reduced pressure and diluted with ethyl acetate. The organic phase was

washed with water, brine solution, dried over anhydrous Na₂SO₄, and then concentrated

under reduced pressure. The residue was subjected to flash silica gel (230 - 400 mesh)

column chromatography (eluting with 0-25% ethyl acetate in hexanes) to afford the title

compound. Yield 45%; Light yellow solid; mp = 190 – 192 °C; IR (neat) 3010, 2924, 1737,

1

1598, 1511, 1240, 1203, 1176, 1051, 1024, 943, 827, 791, 767 cm^-1; H NMR (300 MHz,

CDCl₃)

δ 7.44 - 7.68 (m, 4H), 7.06 (d, J = 7.36 Hz, 1H), 6.98 (d, J = 8.66 Hz, 2H), 6.82 (d, J

= 8.20 Hz, 1H), 3.97 (s, 2H), 3.93 (d, J = 6.05 Hz, 2H), 3.87 (s, 3H), 1.89 - 2.06 (m, 3H),

1.66 - 1.85 (m, 3H), 1.08 - 1.41 (m, 5H); ¹³C NMR (100 MHz, CDCl₃)

δ

192.3, 160.6, 158.6,

151.9, 135.9, 132.9, 132.3, 132.2, 128.5, 126.7, 117.5, 114.4, 110.3, 73.9, 55.3, 37.4, 32.2,

29.7, 26.5, 25.8; HRMS (ESI) calculated for C₂₄H₂₆O₃[M+H]⁺363.1960, found 363.1981.

7.1.5. General synthetic procedure for the preparation of compounds (7a-g)

A solution of corresponding p-methoxybenzyl protected indanone (6a, 6b, 6d-h) (2.403

mmol) and 10% Pd-C (20% w/w) in MeOH/EtOAc (1:1) (20 mL) was stirred for 2 h at room

temperature in the presence of hydrogen gas until complete conversion of the starting

material. The solution was filtered through celite bed and washed with EtOAc. The filtrate

ACCEPTED MANUSCRIPT

was concentrated under reduced pressure which was subjected to flash silica gel (230-400

mesh) column chromatography (eluting with 0-15% ethyl acetate in hexanes) to afford the

title compounds.

7.1.5.1. 7-Hydroxy-2-(4-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7a). This compound

was prepared from 6a. Yield 62%; Off white solid; mp = 98 – 100 °C; IR (neat) 3271, 3026,

1

2969, 2922, 1737, 1650, 1615, 1598, 1458, 1366, 1228, 1216, 991, 808, 779 cm^-1; H NMR

(300 MHz, CDCl₃) δ 9.01 (br. s., 1H), 7.46 (t, J = 7.82 Hz, 1H), 7.11 (d, J = 8.38 Hz, 2H),

6.88 (d, J = 7.26 Hz, 1H), 6.77 (dd, J = 3.03, 8.43 Hz, 3H), 4.83 (br., s. 1H), 3.26 (dd, J =

4.38, 13.88 Hz, 1H), 3.09 - 3.20 (m, 1H), 2.98 - 3.08 (m, 1H), 2.83 (dd, J = 3.17, 17.14 Hz,

13

1H), 2.68 (dd, J = 9.73, 13.92 Hz, 1H); C NMR (100 MHz, CDCl₃)

δ 211.2, 157.6, 154.2,

153.9, 137.8, 131.2, 130.1, 122.2, 117.4, 115.4, 113.6, 48.9, 35.8, 32.0; HRMS (ESI)

calculated for C₁₆H₁₄O₃[M+H]⁺255.1021, found 255.1042.

7.1.5.2. 7-Hydroxy-2-(4-methoxybenzyl)-2,3-dihydro-1H-inden-1-one (7b). This compound

was prepared from 6b. Yield 65%; Off white solid; mp = 61 – 62 °C; IR (neat) 3323, 2935,

1

2844, 1664, 1621, 1509, 1463, 1345, 1241, 1155, 1027, 958, 808, 790 cm^-1; H NMR (300

MHz, CDCl₃)

δ 9.04 (s, 1H), 7.46 (t, J = 7.78 Hz, 1H), 7.16 (d, J = 8.48 Hz, 2H), 6.81 - 6.92

(m, 3H), 6.77 (d, J = 8.10 Hz, 1H), 3.80 (s, 3H), 3.10 - 3.34 (m, 2H), 2.98 - 3.09 (m, 1H),

2.64 – 3.31 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ

211.1, 158.3, 157.6, 153.9, 137.8, 131.1,

129.9, 122.2, 117.4, 114.0, 113.5, 55.2, 48.9, 35.8, 32.1; HRMS (ESI) calculated for

C₁₇H₁₆O₃[M+H]⁺269.1177, found 269.1201.

7.1.5.3. 2-(4-Chlorobenzyl)-7-hydroxy-2,3-dihydro-1H-inden-1-one (7c). This compound was

prepared from 6d. Yield 66%; Colorless oil; HRMS (ESI) calculated for C₁₆H₁₃ClO₂[M+H]⁺

273.0682, found 273.0706. This compound was used for the next step without further

purification.

ACCEPTED MANUSCRIPT

7.1.5.4. 7-Hydroxy-2-(4-methylbenzyl)-2,3-dihydro-1H-inden-1-one (7d). This compound

was prepared from 6e. Yield 64%; Colorless oil; ¹H NMR (300 MHz, DMSO-d₆)

δ 7.38 (t, J

= 7.73 Hz, 1H), 7.05 - 7.16 (m, 4H), 6.79 (d, J = 7.26 Hz, 1H), 6.68 (d, J = 8.10 Hz, 1H),

3.08 (dd, J = 4.05, 13.64 Hz, 1H), 2.85 - 3.04 (m, 2H), 2.55 - 2.71 (m, 2H), 2.25 (s, 3H);

HRMS (ESI) calculated for C₁₇H₁₆O₂[M+H]⁺253.1228, found 253.1251.

7.1.5.5. 7-Hydroxy-2-(4-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one (7e). This

compound was prepared from 6f. Yield 78%; Colorless oil; ¹H NMR (300 MHz, DMSO-d₆)

δ

7.12 - 7.28 (m, 3H), 6.92 (d, J = 8.48 Hz, 2H), 6.47 (t, J = 7.12 Hz, 2H), 5.14 (s, 2H), 3.36 (s,

3H), 3.07 (dd, J = 3.96, 13.64 Hz, 1H), 2.76 - 2.98 (m, 2H), 2.53 - 2.64 (m, 2H); HRMS

(ESI) calculated for C₁₈H₁₈O₄[M+H]⁺299.1283, found 299.1308.

7.1.5.6. 7-Hydroxy-2-(3-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one (7f). This

compound was prepared from 6g. Yield 67%; Brown oil; ¹H NMR (300 MHz, CDCl₃)

δ 7.47

(t, J = 7.78 Hz, 1H), 7.22 (d, J = 8.85 Hz, 1H), 7.10 (d, J = 8.20 Hz, 1H), 6.85 - 6.97 (m, 3H),

6.77 (d, J = 8.20 Hz, 1H), 6.81 (d, J = 8.57 Hz, 1H), 5.17 (s, 2H), 3.49 (s, 3H), 3.34 (dd, J =

4.00, 13.78 Hz, 1H), 3.02 - 3.23 (m, 2H), 2.79 - 2.91 (m, 1H), 2.68 (dd, J = 10.10, 13.83 Hz,

1H); HRMS (ESI) calculated for C₁₈H₁₈O₄[M+H]⁺299.1283, found 299.1308.

7.1.5.7. 7-Hydroxy-2-(2-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one (7g). This

compound was prepared from 6h. Yield 60%; Brown oil; ¹H NMR (300 MHz, CDCl₃)

δ 7.46

(t, J = 7.82 Hz, 1H), 7.16 - 7.26 (m, 2H), 7.11 (dd, J = 4.89, 7.68 Hz, 2H), 6.92 - 7.02 (m,

1H), 6.73 - 6.90 (m, 3H), 5.22 (s, 2H), 3.48 (s, 3H), 3.42 (dd, J = 4.42, 13.74 Hz, 1H), 3.04 -

3.27 (m, 2H), 2.80 - 2.92 (m, 1H), 2.69 (dd, J = 10.20, 13.64 Hz, 1H); excess aromatic

protons showed; HRMS (ESI) calculated for C₁₈H₁₈O₄[M+H]⁺299.1283, found 299.1308.

7.1.6. General synthetic procedure for the preparation of compounds (7h-r)

ACCEPTED MANUSCRIPT

To a solution of the corresponding hydroxyl indanone compound 7b-g (1.67 mmol) in DMF

(10 mL), K₂CO₃(3.35 mmol) and appropriate alkyl or phenyl bromide (1.84 mmol) were

added. The resulting solution was stirred at 60 °C until complete conversion of the starting

material (3 h). After cooling to ambient temperature, the reaction mixture was concentrated

under reduced pressure and diluted with ethyl acetate. The organic phase was washed with

water, brine solution, dried over anhydrous Na₂SO₄, and then concentrated under reduced

pressure. The residue was subjected to flash silica gel (230 - 400 mesh) column

chromatography (eluting with 0-20% ethyl acetate in hexanes) to afford the title compounds.

7.1.6.1. 7-(Cyclohexylmethoxy)-2-(4-methoxybenzyl)-2,3-dihydro-1H-inden-1-one (7h). This

compound was prepared from 7b and (bromomethyl)cyclohexane. Yield 62%; Light brown

oil to light brown solid; mp = 62 – 63 °C; IR (neat) 2923, 2854, 1737, 1703, 1589, 1512,

1458, 1271, 1247, 1197, 1030, 803, 779, 768 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 7.46 (t, J =

7.87 Hz, 1H), 7.16 (d, J = 8.47 Hz, 2H), 6.90 (d, J = 7.54 Hz, 1H), 6.84 (d, J = 8.48 Hz, 2H),

6.75 (d, J = 8.20 Hz, 1H), 3.89 (t, J = 6.01 Hz, 2H), 3.80 (s, 3H), 3.35 (dd, J = 4.05, 14.02

Hz, 1H), 3.02 - 3.14 (m, 1H), 2.84 - 2.96 (m, 1H), 2.72 - 2.83 (m, 1H), 2.58 (dd, J = 10.57,

13.92 Hz, 1H), 1.89 - 2.04 (m, 3H), 1.69 - 1.82 (m, 3H), 1.09 - 1.36 (m, 5H); ¹³C NMR (100

MHz, CDCl₃)

δ 205.2, 158.1, 158.1, 156.1, 136.3, 132.1, 129.9, 124.9, 117.9, 113.9, 109.9,

73.8, 55.2, 49.5, 37.4, 36.2, 31.9, 29.7, 29.7, 26.4, 25.7, 25.7; HRMS (ESI) calculated for

C₂₄H₂₈O₃[M+H]⁺365.2116, found 365.2139.

7.1.6.2. 2-(4-Chlorobenzyl)-7-(cyclohexylmethoxy)-2,3-dihydro-1H-inden-1-one (7i). This

compound was prepared from 7c and (bromomethyl)cyclohexane. Yield 55%; Light brown

oil; IR (neat) 2905, 2838, 1695, 1615, 1593, 1512, 1480, 1287, 1234, 1193, 1175, 1061,

1032, 939, 808, 768 cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 7.47 (t, J = 7.93 Hz, 1H), 7.26 (d, J

= 7.84 Hz, 2H), 7.17 (d, J = 8.28 Hz, 2H), 6.90 (d, J = 7.56 Hz, 1H), 6.76 (d, J = 8.29 Hz,

1H), 3.84 - 3.92 (m, 2H), 3.36 (dd, J = 4.15, 14.15 Hz, 1H), 3.09 (dd, J = 7.80, 17.07 Hz,

ACCEPTED MANUSCRIPT

1H), 2.86 - 2.93 (m, 1H), 2.74 (dd, J = 4.39, 17.07 Hz, 1H), 2.63 (dd, J = 10.37, 14.02 Hz,

1H), 1.91 - 2.02 (m, 3H), 1.70 - 1.80 (m, 3H), 1.09 - 1.34 (m, 5H); ¹³C NMR (100 MHz,

CDCl₃)

δ 204.7, 158.1, 155.8, 138.5, 136.5, 132.0, 130.3, 128.6, 124.8, 117.9, 110.0, 73.8,

49.1, 37.3, 36.4, 31.8, 29.7, 29.7, 26.4, 25.7, 25.7; HRMS (ESI) calculated for C₂₃H₂₅ClO₂

[M+H]⁺369.1621, found 369.1642.

7.1.6.3. 7-(Cyclohexylmethoxy)-2-(4-methylbenzyl)-2,3-dihydro-1H-inden-1-one (7j). This

compound was prepared from 7d and (bromomethyl)cyclohexane. Yield 69%; Off white

solid; mp = 76 – 78 °C; IR (neat) 3014, 2918, 2849, 1738, 1686, 1592, 1513, 1479, 1459,

1365, 1350, 1268, 1230, 1199, 1095, 1067, 995, 805, 766 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ

7.46 (t, J = 7.82 Hz, 1H), 7.08 - 7.17 (m, 4H), 6.90 (d, J = 7.54 Hz, 1H), 6.75 (d, J = 8.20

Hz, 1H), 3.82 - 3.95 (m, 2H), 3.39 (dd, J = 3.96, 13.92 Hz, 1H), 3.02 - 3.14 (m, 1H), 2.86 -

2.98 (m, 1H), 2.73 - 2.84 (m, 1H), 2.57 (dd, J = 10.71, 13.97 Hz, 1H), 2.33 (s, 3H), 1.86 -

2.06 (m, 3H), 1.67 - 1.84 (m, 3H), 1.05 - 1.40 (m, 5H); ¹³C NMR (100 MHz, CDCl₃)

δ 205.2,

158.1, 156.1, 137.0, 136.3, 135.7, 129.2, 128.8, 124.9, 117.9, 109.9, 73.8, 49.4, 37.4, 36.7,

32.0, 29.7, 29.7, 26.4, 25.7, 25.7, 20.9; HRMS (ESI) calculated for C₂₄H₂₈O₂[M+H]⁺

349.2167, found 349.2191.

7.1.6.4. 7-(Cyclohexylmethoxy)-2-(4-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one

(7k). This compound was prepared from 7e and (bromomethyl)cyclohexane. Yield 65%;

Colorless oil; IR (neat) 2922, 2851, 1707, 1591, 1509, 1459, 1229, 1151, 1077, 996, 773 cm^-

¹; ¹H NMR (300 MHz, CDCl₃)

δ 7.46 (t, J = 7.87 Hz, 1H), 7.16 (d, J = 8.38 Hz, 2H), 6.97 (d,

J = 8.38 Hz, 2H), 6.90 (d, J = 7.45 Hz, 1H), 6.75 (d, J = 8.29 Hz, 1H), 5.16 (s, 2H), 3.84 -

3.94 (m, 2H), 3.49 (s, 3H), 3.35 (dd, J = 3.87, 14.02 Hz, 1H), 3.03 - 3.15 (m, 1H), 2.84 - 2.95

(m, 1H), 2.73 - 2.83 (m, 1H), 2.58 (dd, J = 10.48, 14.02 Hz, 1H), 1.89 - 2.03 (m, 3H), 1.68 -

1.83 (m, 3H), 1.05 - 1.41 (m, 5H); ¹³C NMR (100 MHz, CDCl₃)

δ 205.2, 158.1, 156.1, 155.8,

ACCEPTED MANUSCRIPT

136.3, 133.4, 129.9, 124.9, 117.9, 116.3, 109.9, 94.5, 73.8, 55.9, 49.4, 37.3, 36.3, 31.9, 29.7,

29.7, 26.4, 25.7, 25.7; HRMS (ESI) calculated for C₂₅H₃₀O₄[M+H]⁺395.2222, found

395.2243.

7.1.6.5. 7-(Cyclohexylmethoxy)-2-(3-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one

(7l). This compound was prepared from 7f and (bromomethyl)cyclohexane. Yield 68%;

1

Colorless oil; H NMR (300 MHz, CDCl₃)

δ 7.47 (t, J = 7.87 Hz, 1H), 7.22 (t, J = 7.64 Hz,

1H), 6.87 - 6.95 (m, 4H), 6.76 (d, J = 8.20 Hz, 1H), 5.17 (s, 2H), 3.83 - 3.95 (m, 2H), 3.49 (s,

3H), 3.42 (dd, J = 3.82, 14.06 Hz, 1H), 3.06 - 3.16 (m, 1H), 2.90 - 2.98 (m, 1H), 2.74 - 2.85

(m, 1H), 2.56 (dd, J = 10.85, 13.92 Hz, 1H), 1.91 - 2.02 (m, 3H), 1.70 - 1.82 (m, 3H), 1.11 -

1.36 (m, 5H); HRMS (ESI) calculated for C₂₅H₃₀O₄[M+H]⁺395.2222, found 395.2243.

7.1.6.6. 7-(Cyclohexylmethoxy)-2-(2-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one

(7m). This compound was prepared from 7g and (bromomethyl)cyclohexane. Yield 60%;

Colorless oil; ¹H NMR (300 MHz, CDCl₃)

δ 7.46 (t, J = 7.82 Hz, 1H), 7.20 (t, , J = 7.65 Hz,

2H), 7.06 - 7.14 (m, 1H), 6.86 - 7.01 (m, 2H), 6.75 (d, J = 8.20 Hz, 1H), 5.21 (s, 2H), 3.85 -

3.89 (m, 2H), 3.53 (d, J = 3.45 Hz, 1H), 2.98 - 3.13 (m, 2H), 2.78 - 2.85 (m, 1H), 2.58 (dd, J

= 10.57, 13.55 Hz, 1H), 1.87 - 2.05 (m, 3H), 1.69 - 1.82 (m, 3H), 1.09 - 1.37 (m, 5H); HRMS

(ESI) calculated for C₂₅H₃₀O₄[M+H]⁺395.2222, found 395.2243.

7.1.6.7. 7-(2-Cyclohexylethoxy)-2-(4-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one

(7n). This compound was prepared from 7e and (2-bromoethyl)cyclohexane. Yield 59%;

Colorless oil; ¹H NMR (400 MHz, CDCl₃)

δ 7.47 (t, J = 7.44 Hz, 1H), 7.17 (d, J = 8.29 Hz,

2H), 6.97 (d, J = 8.05 Hz, 2H), 6.91 (d, J = 7.56 Hz, 1H), 6.77 (d, J = 8.29 Hz, 1H), 5.16 (s,

2H), 4.14 (t, J = 6.83 Hz, 2H), 3.49 (s, 3H), 3.34 (dd, J = 4.02, 14.02 Hz, 1H), 3.04 - 3.13 (m,

1H), 2.86 - 2.95 (m, 1H), 2.78 (dd, J = 4.02, 17.20 Hz, 1H), 2.58 (dd, J = 10.49, 13.90 Hz,

ACCEPTED MANUSCRIPT

1H), 1.16 - 1.82 (m, 8H), 1.08 – 1.31 (m, 5H); HRMS (ESI) calculated for C₂₆H₃₂O₄[M+H]⁺

409.2379, found 409.2404.

7.1.6.8. 7-(Benzyloxy)-2-(4-(methoxymethoxy)benzyl)-2,3-dihydro-1H-inden-1-one (7o). This

compound was prepared from 7e and (bromomethyl)benzene. Yield 62%; Light brown oil; ¹H

NMR (300 MHz, CDCl₃)

δ 7.49 - 7.58 (m, 2H), 7.35 - 7.48 (m, 3H), 7.28 - 7.34 (m, 1H),

7.18 (d, J = 8.48 Hz, 2H), 6.91 - 7.02 (m, 3H), 6.80 (d, J = 8.20 Hz, 1H), 5.29 (s, 2H), 5.17

(s, 2H), 3.49 (s, 3H), 3.36 (dd, J = 4.00, 13.97 Hz, 1H), 3.05 - 3.18 (m, 1H), 2.89 - 3.01 (m,

1H), 2.81 (dd, J = 4.00, 17.04 Hz, 1H), 2.63 (dd, J = 10.38, 13.92 Hz, 1H); HRMS (ESI)

calculated for C₂₅H₂₄O₄[M+H]⁺389.1753, found 389.1776.

7.1.6.9. 2-(4-(Methoxymethoxy)benzyl)-7-phenethoxy-2,3-dihydro-1H-inden-1-one (7p). This

1

compound was prepared from 7e and (2-bromoethyl)benzene. Yield 61%; Colorless oil; H

NMR (300 MHz, CDCl₃)

δ 7.31 - 7.48 (m, 5H), 7.22 - 7.28 (m, 2H), 7.16 (d, J = 8.57 Hz,

2H), 6.98 (d, J = 8.57 Hz, 2H), 6.92 (d, J = 7.54 Hz, 1H), 6.74 (d, J = 8.10 Hz, 1H), 5.17 (s,

2H), 4.28 (dt, J = 1.86, 7.17 Hz, 2H), 3.49 (s, 3H), 3.35 (dd, J = 4.10, 14.06 Hz, 1H), 3.23 (t,

J = 7.12 Hz, 2H), 3.03 - 3.15 (m, 1H), 2.86 - 2.98 (m, 1H), 2.74 - 2.83 (m, 1H), 2.60 (dd, J =

10.38, 13.92 Hz, 1H); HRMS (ESI) calculated for C₂₆H₂₆O₄[M+H]⁺403.1909, found

403.1932.

7.1.6.10. 2-(3-(Methoxymethoxy)benzyl)-7-phenethoxy-2,3-dihydro-1H-inden-1-one (7q).

This compound was prepared from 7f and (2-bromoethyl)benzene. Yield 56%; Colorless oil;

¹H NMR (300 MHz, CDCl₃)

δ 7.33 - 7.49 (m, 5H), 7.19 - 7.25 (m, 2H), 6.88 - 6.98 (m, 4H),

6.75 (d, J = 8.10 Hz, 1H), 5.18 (s, 2H), 4.29 (dt, J = 1.96, 7.17 Hz, 2H), 3.49 (s, 3H), 3.42

(dd, J = 3.91, 13.97 Hz, 1H), 3.23 (t, J = 7.03 Hz, 2H), 3.05 - 3.17 (m, 1H), 2.92 - 3.01 (m,

1H), 2.74 - 2.85 (m, 1H), 2.51 - 2.64 (m, 1H); HRMS (ESI) calculated for C₂₆H₂₆O₄[M+H]⁺

403.1909, found 403.1932.

ACCEPTED MANUSCRIPT

7.1.6.11. 2-(2-(Methoxymethoxy)benzyl)-7-phenethoxy-2,3-dihydro-1H-inden-1-one (7r).

This compound was prepared from 7g and (2-bromoethyl)benzene. Yield 65%; Colorless oil;

¹H NMR (300 MHz, CDCl₃) δ 7.38 - 7.48 (m, 3H), 7.29 - 7.38 (m, 2H), 7.16 - 7.26 (m, 3H),

7.07 - 7.13 (m, 1H), 6.89 - 7.00 (m, 2H), 6.74 (d, J = 8.20 Hz, 1H), 5.22 (s, 2H), 4.28 (t, J =

7.17 Hz, 2H), 3.42 - 3.55 (m, 4H), 3.23 (t, J = 7.17 Hz, 2H), 3.07 - 3.14 (m, 1H), 2.76 - 2.92

(m, 2H), 2.62 (dd, J = 10.52, 13.69 Hz, 1H); HRMS (ESI) calculated for C₂₆H₂₆O₄[M+H]⁺

403.1909, found 403.1932.

7.1.7. General synthetic procedure for the preparation of compounds (7s-z)

A solution of the corresponding MOM compound 7k-r (0.507 mmol) and Conc.HCl (0.2 mL)

in MeOH was stirred at 60 °C for 3 h. The solution was concentrated under vacuum, diluted

with EtOAc and then washed with water. The organic layer was dried over anhydrous

Na₂SO₄, filtered and evaporated by vacuum. The residue was subjected to flash silica gel

(230-400 mesh) column chromatography (eluting with 0 - 15% ethyl acetate in hexanes) to

afford the title compounds.

7.1.7.1. 7-(Cyclohexylmethoxy)-2-(4-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7s). This

compound was prepared from 7k. Yield 85%; White solid; mp = 185 – 186.5 °C; IR (neat)

1

3357, 2923, 2843, 1683, 1598, 1456, 1271, 1218, 1060, 1028, 840, 775 cm^-1; H NMR (300

MHz, CDCl₃)

δ 7.46 (t, J = 7.87 Hz, 1H), 7.10 (d, J = 8.38 Hz, 2H), 6.90 (d, J = 7.54 Hz,

1H), 6.71 - 6.81 (m, 3H), 5.05 (s, 1H), 3.83 - 3.93 (m, 2H), 3.32 (dd, J = 4.00, 13.97 Hz, 1H),

3.02 - 3.14 (m, 1H), 2.84 - 2.95 (m, 1H), 2.72 - 2.82 (m, 1H), 2.58 (dd, J = 10.29, 13.92 Hz,

1H), 1.86 - 2.03 (m, 3H), 1.66 - 1.83 (m, 3H), 1.05 - 1.36 (m, 5H); ¹³C NMR (100 MHz,

CDCl₃)

δ 205.7, 158.1, 156.2, 154.3, 136.5, 131.8, 130.1, 124.9, 117.9, 115.3, 109.9, 73.9,

49.5, 37.3, 36.2, 31.9, 29.7, 29.7, 26.4, 25.7, 25.7; HRMS (ESI) calculated for C₂₃H₂₆O₃

[M+H]⁺351.1960, found 351.1981.

ACCEPTED MANUSCRIPT

7.1.7.2. 7-(Cyclohexylmethoxy)-2-(3-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7t). This

compound was prepared from 7l. Yield 63%; White solid; mp = 139 – 140 °C; IR (neat)

3355, 2920, 2841, 1686, 1593, 1515, 1480, 1449, 1274, 1237, 1201, 1082. 1064, 1032, 998,

774 cm^-1; ¹H NMR (300 MHz, DMSO-d₆)

δ 9.28 (s, 1H), 7.52 (t, J = 7.82 Hz, 1H), 7.06 (t, J

= 7.74 Hz, 1H), 6.98 (d, J = 7.45 Hz, 1H), 6.90 (d, J = 8.20 Hz, 1H), 6.62 - 6.68 (m, 2H),

6.59 (dd, J = 2.00, 7.78 Hz, 1H), 3.83 - 3.90 (m, 2H), 3.04 - 3.09 (m, 1H), 2.98 - 3.04 (m,

1H), 2.81 - 2.91 (m, 1H), 2.65 - 2.75 (m, 1H), 2.55 (d, J = 9.97 Hz, 1H), 1.64 - 1.89 (m, 6H),

13

1.05 - 1.30 (m, 5H); C NMR (100 MHz, DMSO-d₆)

δ 204.0, 157.5, 157.3, 155.9, 141.3,

136.6, 129.4, 124.2, 119.6, 118.1, 115.8, 113.2, 110.3, 72.9, 48.4, 37.0, 36.1, 31.3, 29.0, 26.0,

25.3; HRMS (ESI) calculated for C₂₃H₂₆O₃[M+H]⁺351.1960, found 351.1981.

7.1.7.3. 7-(Cyclohexylmethoxy)-2-(2-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7u). This

compound was prepared from 7m. Yield 61%; Off white solid; mp = 211.5 – 213 °C; IR

(neat) 3356, 2921, 2853, 1684, 1593, 1481, 1455, 1272, 1238, 1202, 1082. 1064, 1032, 997,

775, 750 cm^-1; ¹H NMR (300 MHz, DMSO-d₆)

δ 9.37 (s, 1H), 7.52 (t, J = 7.87 Hz, 1H), 7.10

(d, J = 7.36 Hz, 1H), 6.95 - 7.06 (m, 2H), 6.90 (d, J = 8.20 Hz, 1H), 6.80 (d, J = 7.92 Hz,

1H), 6.71 (t, J = 7.36 Hz, 1H), 3.87 (d, J = 6.05 Hz, 2H), 3.10 - 3.21 (m, 1H), 2.88 - 3.04 (m,

13

2H), 2.66 - 2.80 (m, 1H), 2.36 - 2.47 (m, 1H), 1.62 - 1.89 (m, 6H), 1.03 - 1.31 (m, 5H); C

NMR (100 MHz, DMSO-d₆)

δ 204.5, 157.3, 156.1, 155.5, 136.5, 130.5, 127.3, 126.1, 124.3,

119.0, 118.1, 115.0, 110.3, 72.9, 47.1, 37.0, 31.4, 31.1, 29.0, 26.0, 25.3; HRMS (ESI)

calculated for C₂₃H₂₆O₃[M+H]⁺351.1960, found 351.1981.

7.1.7.4. 7-(2-Cyclohexylethoxy)-2-(4-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7v). This

compound was prepared from 7n. Yield 85%; White solid; mp = 133 – 136 °C; IR (neat)

1

3341, 2918, 2848, 1686, 1592, 1514, 1461, 1272, 1230, 1062, 1027, 977, 838, 768 cm^-1; H

NMR (400 MHz, CDCl₃)

δ 7.46 (t, J = 7.80 Hz, 1H), 7.10 (d, J = 8.29 Hz, 2H), 6.91 (d, J =

Article Doi

Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors

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