Divergent Syntheses of Spiroindanones and 2-Substituted 1

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Divergent Syntheses of Spiroindanones and 2-Substituted 1Indanones by Ruthenium-Catalyzed Tandem Coupling and Cyclization of Aromatic Acids with #,ß-Unsaturated Ketones Jia-Ni Wang, Si-Qi Chen, Zhong-Wen Liu, and Xian-Ying Shi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02820 • Publication Date (Web): 08 Jan 2019 Downloaded from http://pubs.acs.org on January 10, 2019

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The Journal of Organic Chemistry

Divergent Syntheses of Spiroindanones and 2-Substituted 1-Indanones by Ruthenium-Catalyzed Tandem Coupling and Cyclization of Aromatic Acids with α,ß-Unsaturated Ketones Jia-Ni Wang, Si-Qi Chen, Zhong-Wen Liu, and Xian-Ying Shi* Key Laboratory for Macromolecular Science of Shaanxi Province, Research Center for Applied Catalysis, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi’an 710062, China

Corresponding author. Tel.: +86-29-8153-0726; E-mail: [email protected] O C2H5

R O R'=C2H5

CH3

[RuCl2(p-cymene)]2

Mn(OAc)2, CH3CN 20 h, Ar, 150 oC

CO2H +

R

O

O [RuCl2(p-cymene)]2 R' MnCO3, CH3CN/H2O 20 h, Ar, 150 oC

Tandem domino cyclization Multiple bonds formed in one pot

R

O R'

High step-economy Broad substrate scope

ABSTRACT: The one-step strategy for the facile syntheses of structurally diverse 1-indanones in moderate to good isolated yields was developed via a ruthenium-catalyzed tandem coupling and cyclization of simple aromatic acids with α,ß-unsaturated ketones. The tandem cyclization involves one-pot sequential reactions of C‒H activation, conjugate addition, Dieckmann condensation, Michael addition, intramolecular Aldol reaction or hydrolysis. Switchable access to spiroindanones and 2-substituted 1-indanones could be acheived by manganese additive and H2O. Mn(II) additive is found to play an important role in this transformation, and a trace amount of water can promote the formation of 2-substituted 1-indanones. This process features the one-pot efficient construction of multiple C‒C bonds, high step-economy, commercially available starting materials, and a broad substrate scope. INTRODUCTION As an important class of cyclic compounds, 1-indanones have been found in many natural products and biologically active molecules.1 They are also frequently employed as building blocks in functional materials and pharmaceuticals.2 The intramolecular cyclization reactions, such as Nazarov cyclization of aryl vinyl ketones and the intramolecular Friedel-Crafts acylation of the 3-aryl aromatic acids or corresponding acyl chlorides,3-4 are common methods to generate 1-indanones. Alternatively, the intramolecular hydroacylation of alkenes, the addition of aryl compounds to aryl alkynyl ketones, the oxidative cyclizations of cis-3-en-1-ynes, or the isomerization of α-arylpropargyl alochols also afford 1-indanone motif. 5-8 However, the prefunctionalized substrates and/or superstoichiometric Lewis acids are often required in these transformations, which limits their synthetic utility. Therefore, developing more 1

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concise methods for the synthesis of the diverse 1-indanone skeleton from commercially available starting materials has been an intense topic.9 Recently, transition-metal-catalyzed intermolecular tandem cyclization reactions based on C–H activation, which enable the formation of several bonds in one pot by using a single catalyst, have emerged as a promising tool to construct complex skeleton because it may not only significantly simplify and shorten the synthetic route but also allow the use of readily available substrates.10 Employing this strategy, Greaney’s group reported that simple aryl acetophenones could react with a variety of Michael acceptors to give 1-indanones though triple C–H functionalization.11 Li and his coworkers disclosed rhodium-catalyzed tandem reactions of phenacyl ammonium/phosphonium salts with diazoesters or active alkenes for the formation of 1-indanones.12 Aromatic acids have been widely used as attractive candidates in tandem cyclization reactions due to their wide availability and high reactivity.13 In this context, coupling of aromatic acids and alkynes/alkenes represents a particularly useful contribution to isocoumarins/3,4-dihydroisocoumarins synthesis,14 while the reactions of benzoic acids with acrylates exclusively delivered phthalide derivatives through the sequence of ortho-olefination of carboxyl and subsequent Michael addition (Scheme 1, a).15 Recently, we reported a ruthenium-catalyzed conjugate addition of C‒H bonds to α,ß-unsaturated ketones directed by a carboxyl (Scheme 1, b).16 Inspired by this encouraging work, we envisioned that the enols formed via tautomeric transformation of ketones may attack the C=O bond of carboxyls, leading to the formation of 1-indanones via a Dieckmann condensation reaction. However, carboxylic acids are rarely reported as an electrophile for the Dieckmann condensation.17 Herein, we describe the ruthenium-catalyzed tandem domino Previous work

O

O CO2H

(a) R

O

+

OR'

Rh or Ru oxidant

R

O

or OR'

O R O

O CO2H

(b) R

O

+

[RuCl2(p-cymene)]2 R'

H2O, air, 95 oC, 12 h

OR'

CO2H R

R' O

This work R

CO2H +

O

O

O

Ru catalyst R'

C2H5 or R

R

R'

O CH3 R'=C2H5 CO2H R

CO2H R'

O

R

O

R' OH

Scheme 1. Reactions between aromatic acids and active alkenes 2


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cyclization for the one-step synthesis of structurally diverse 1-indanons from simple aromatic acids and α,ß-unsaturated ketones (Scheme 1). Switchable access to spiroindanones and 2-substituted 1-indanones can be tuned by manganese additive and H2O. RESULTS AND DISCUSSION To test the proposed strategy, we chose the o-toluic acid (1a) and ethyl vinyl ketone (2a) as model substrates to initiate our investigation. After a considerable number of experiments, we found that 4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3a) were formed in 60% NMR yield (Table 1, entry 1). The yield of 3a’ (12%) and a trace amount of 2-substituted 1-indanone (4a) were observed in the crude reaction mixture. Moreover, 3a’ was also found in our reported catalytic system.16 Notably, four new C‒C bonds were formed, and no theoretical waste except for water is generated in this domino cyclization. Table 1. Optimization Studies on the spiroindanones a CH3

O

CH3 +

C2H5

C2H5 additive, solvent 24 h, Ar, 150 oC

CO2H 1a

O

[RuCl2(p-cymene)]2

2a

3a CH3

O

CH3

O

CH3 O O

O O 3a'

Entry

Additive

Solvent

1

Mn(OAc)2

2

C2H5 4a

C2H5

Yield(%)b

Conversion of 1a (%)

3a

3a’

4a

CH3CN

95

60

12

trace

-

CH3CN

41

ND

4

ND

3

Mn(OAc)2

dioxane

95

36

17

5

4

Mn(OAc)2

DCE

100

45

trace

ND

5

Mn(OAc)2

toluene

100

48

14

10

6

Mn(OAc)2

C6H5Cl

100

43

16

ND

7

Mn(OAc)2

o-xylene

100

56

16

11

8

Mn(OAc)2

tAmylOH

100

46

14

12

9

MnCO3

CH3CN

84

39

19

trace

10

Zn(OAc)2

CH3CN

73

28

5

11

11

Co(OAc)2

CH3CN

86

36

8

11

12

PivONa

CH3CN

100

14

11

ND

13

Fe(OAc)2

CH3CN

87

18

53

4

14

NaOAc

CH3CN

100

13

8

ND

15c

Mn(OAc)2

CH3CN

100

63

9

trace

aReactions

were carried out with 1a (0.1 mmol), 2a (0.2 mmol), [RuCl2(p-cymene)]2 (5 mol%), additive (0.75 equiv), solvent

(0.6 mL), at 150 °C for 24 h, under argon in pressure tubes. bDetermined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. c0.25 mmol 2a were used, 20 h. tAmylOH =2-methyl-2-butanol. 3



Control experiments indicated that the use of Mn(OAc)2 is very crucial for the formation of 3a. The reaction without Mn(OAc)2 failed to afford 3a (Table 1, entry 2). Subsequently, various conditions concerning the additives, solvents, reaction time were examined to improve the yield of 3a. Screening of solvents revealed that CH3CN was the best choice; other solvents such as 1,4-dioxane, DCE, toluene, C6H5Cl, o-xylene and tAmylOH were less effective (Table 1, entries 3-8). Replacing Mn(OAc)2 with other additives such as MnCO3, Zn(OAc)2, Co(OAc)2, PivONa, Fe(OAc)2 and NaOAc, no obviously improved results were observed (Table 1, entries 9-14). If manganese formate dihydrate or pi-acid such as InCl3, InCl3·4H2O, InOTf3 and Zn(OTf)2 was added as an additive, respectively, desired products were not detected. Further variations of the catalyst such as RuCl2(COD), [Cp*RhCl2]2, [Cp*Rh(CH3CN)3](SbF6)2 and Pd(OAc)2 failed to enhance the reaction outcome. Finally, shortening the reaction time to 20 h and increasing 2a to 0.25 equiv resulted in 63% yield of 3a (Table 1, entry 15). After the establishment of the optimal reaction condition, the scope of this tandem cyclization for synthesizing spiroindanones was studied. As shown in Table 2, ortho-substituted aromatic acids with halogens or electron-donating groups such as ethyl, benzyl, phenethyl, phenyl and phenoxy reacted efficiently with ethyl vinyl ketone to give the desired products in moderate yields (3b-3j, 50%-65%). 2,3-, 2,4-disubstituted aromatic acids were also well tolerated, affording the target products in 53%-63% yields (3k-3u). In the cases of the 2,5-disubstituted aromatic acids, to our surprise, the reactions proceeded smoothly regardless of steric hindrance (3v-3y, 54%-59%). The structure of 3q was confirmed by single crystal X-ray diffraction (CCDC 1875024). Notably, when the reaction was performed in a larger scale of 6.0 mmol, almost the same isolated yield of 62% for 3q was obtained. As for benzoic acid, meta- or para-substituted benzoic acids, there are two possible sites for the C‒H bond activation at the ortho-position of the carboxyl. Employing benzoic acid, para- or 3-methoxyl substituted benzoic acids as substrates, 7'-(3-oxopentyl) substituted spiroindanones were obtained as main products (3aa-3ag). In the case of 3-methyl substituted substrates, such as 3-methyl benzoic acid or 3,5-dimethylbenzoic acid, mixed products of 3ah-3ai were observed. These results also indicate that direct addition of C–H bond to polar C=C bond rather than ortho-olefination of carboxyl takes place in this catalytic system. Unforturanately, aromatic acids with electron-withdrawing groups such as NO2, and CN failed to give the cyclization product. The reason may lie in that the combination of carboxyl group with an additional electron-withdrawing group makes the aryl ring highly electron-deficient and retards the attacking of the electrophilic ruthenium. 4


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Table 2. Substrate scope for the spiroindanonesa

R

R

O

O

CO2H +

[RuCl2(p-cymene)]2

O

O

O 3b-3ai

CH3

CH3

O

O

R C2H5 O 3k 63% CH3

O

C2H5 O CH3

CH3

O

3q: R=CH3, 63%(62%)b 3r: R=CH3O, 62% 3s: R=F, 56% 3t: R=Cl, 56% 3u: R=Br, 54%

C2H5 OCH3 O

O

3w: R=F, 59% 3x: R=Cl, 55% 3y: R=Br, 55%

O 3z 65%

C2H5

R

3aa: R=H, 49%c 3ab: R=CH3, 56%c 3ac: R=C2H5, 57%c 3ad: R=CH3O, 52%c H3CO c C2H5 3ae: R=C2H5O, 54%

O

O C2H5 R

C2H5

C2H5 O

CH3

O

H3C

C2H5

CH3

O

R 3ah-3ai

O

3af: R=H, 35%c 3ag: R=CH3O, 54%c

O

R

C2H5

O

CH3 O

H3C

O CH3

CH3

O

CH3

3v 54% CH3

O C2H5

R

CH3

OCH3 O

O

R

3l: R=CH3, 57% 3m: R=CH3O, 60% 3n: R=F, 57% 3o: R=Cl, 59% 3p: R=Br, 53%

C2H5

CH3

CH3

3g: R=F, 50% 3h: R=Cl, 51% 3i: R=Br,50% 3j: R=I,55%

3b: R=C2H5, 62% 3c: R=PhCH2,57% 3d: R=PhCH2CH2,65% 3e: R=Ph,61% 3f: R=PhO,56%

C2H5

C2H5

R

C2H5 Mn(OAc)2, CH3CN 20 h, Ar, 150 oC

CH3

3ah'-3ai'

R=H, 48% (3ah:3ah' = 28:20)cd R=CH3, 46% (3ai:3ai' = 31:15)cd aReaction

conditions: aromatic acids (0.2 mmol), α,ß-unsaturated ketones (0.5 mmol), [RuCl2(p-cymene)]2 (5 mol%),

Mn(OAc)2 (0.75 equiv), CH3CN (0.6 mL), 150 °C, 20 h, Ar, isolated yield. b6 mmol acid was used, 18 mL CH3CN. c0.7 mmol acid was used. dDetermined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.

Next, the generality of α,ß-unsaturated ketones were explored under the standard reaction conditions. It was found that methyl vinyl ketone could react well with o-toluic acid to facilitate the desired product 3z in 65% yield. Although this reaction could be extended to long chain α,ß-unsaturated ketones such as hept-1-en-3-one, oct-1-en-3-one, undec-1-en-3-one and 5-phenylpent-1-en-3-one, the yields of the target products were comparatively low (< 30% NMR yield). In most cases, the high conversion of aromatic acids and the formation of by-products (3-substituted phthalides and 2-substituted 1-indanones) were observed in 5



the synthesis of spiroindanones (see Supporting Information Table S1). Table 3. Optimization Studies on the 2-substituted 1-Indanonesa O

CH3 + CO2H

[RuCl2(p-cymene)]2 R

1a

CH3

O O

additive, solvent/H2O 24 h, Ar, 150 oC 4a: R = C2H5 4b: R = nC5H11

2a: R = C2H5 2b: R = nC5H11 CH3

CH3

O

O

C2H5 3a

Entry

O

CH3

Additive

Solvent

1

Mn(OAc)2

2

R

O O 3a'

R

Yield(%)b

Conversion of 1a (%)

4a

3a

3a’

CH3CN

100

44

26

12

--

CH3CN

11

ND

ND

ND

3

MnCO3

CH3CN

100

48

26

10

4

(HCO2)2Mn·2H2O

CH3CN

83

12

6

18

5

Co(OAc)2

CH3CN

100

35

27

8

6

Zn(OAc)2

CH3CN

65

30

10

7

7

Co(acac)2

CH3CN

63

20

15

8

8

K2CO3

CH3CN

100

ND

7

36

9

Na2CO3

CH3CN

100

ND

20

10

10

MnCO3

dioxane

19

ND

ND

trace

11

MnCO3

DME

59

ND

8

25

12

MnCO3

tAmylOH

32

ND

trace

16

13

MnCO3

o-xylene

94

ND

43

20

14

MnCO3

m-xylene

36

ND

12

18

15

MnCO3

toluene

80

ND

26

24

16c

MnCO3

CH3CN

100

61

22

6

17d

MnCO3

CH3CN

100

81

trace

8

aReactions

were carried out with 1a (0.1 mmol), 2a (0.2 mmol), [RuCl2(p-cymene)]2 (5 mol%), additive (0.5 equiv), solvent

(0.6 mL), H2O (38 μL) at 150 °C for 24 h, under argon in pressure tubes. bDetermined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. c1.0 equiv MnCO3 and 0.25 mmol 2a were used, 20 h. d1.0 equiv MnCO3 and 0.25 mmol 2b were used, 20 h.

Surprisingly, when a trace amount of water was added to the reaction system, the yield of 2-substituted 1-indanone (4a) was improved to 44% accompanied with 3a and 3a’ (Table 3, entry 1). The structure of 4a was confirmed by single crystal X-ray diffraction (CCDC 1855651). Encouraged by these interesting results, we further optimize the reaction conditions to improve the yield and selectivity of 4a. Changing the Mn(OAc)2 additive to MnCO3, the yield of 4a was improved to 48% yield. The utilization of other additives, such as (HCO2)2Mn·2H2O, Co(OAc)2, Zn(OAc)2, or Co(acac)2, were relatively ineffective (Table 6


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3, entries 4-7). No desired product was detected using K2CO3 or Na2CO3 as additives (Table 3, entries 8-9). Among the commonly used solvents, CH3CN was superior to others (Table 3, entries 10-15). Then, some reaction parameters including the amount of catalyst or MnCO3, the reaction stoichiometry and reaction time were screened. Increasing the amount of MnCO3 and 2a to 1.0 equiv and 2.5 equiv, respectively, 61% yield of 4a was obtained after 20 h (Table 3, entry 16). Finally, satisfactory yield of 4b was generated by replacing 2a with oct-1-en-3-one (Table 3, entry 17). Thereafter, we investigated the generality of this transformation with different aromatic acids and α,ß-unsaturated ketones. As shown in Table 4, aromatic acids showed a similar behavior to that of spiroindanones. No desired cyclization product was observed when electron-deficient aromatic acids such as 2-nitrobenzoic acid and 4-cyanobenzoic acid were used. Ortho-substituted and disubstituted benzoic acids with electron-donating groups or halogens all reacted smoothly with oct-1-en-3-one to deliver the corresponding products in moderate to excellent yields (4c-4z, 40%-83%). 3 mmol scale reaction was conducted using 5-fluoro-2-methylbenzoic acid as substrate, and the reaction proceeded smoothly to give the product 4x in good yield (75%). However, 2,5-dimethylbenzoic acid and 2,5-dimethoxybenzoic acid delivered lower yields of products (NMR yield < 35%). Benzoic acid and para- or 3-methoxyl substituted benzoic acids also afforded dialkylated products (4aa-4ah, 36 - 61%) while 3,5-dimethyl benzoic acid produced a mixture of mono- and dialkylated products (4ai). The scope of the present cyclization reaction was further examined with various α,ß-unsaturated ketones and 5-fluoro-2-methylbenzoic acid. A variety of linear α,ß-unsaturated ketones could be transformed into the desired products 4aj-4ap in 58-82% yields. 5-Phenylpent-1-en-3-one afforded excellent yield of 82% (4ap). Phenyl vinyl ketone was proved to be viable substrate with this transformation and provided the desired product in a satisfactory yield (4aq, 76%). Moreover, the high conversion of aromatic acids and the side product of 3-substituted phthalides were observed in most cases (see Supporting Information Table S2). However, branched α,ß-unsaturated ketones, e.g. 5-methylhex-1-en-3-one, provided lower yield (13% NMR yield), which may be due to the steric effect. When other active alkenes such as methyl acrylate, acrylamide, diethyl vinylphosphonite, methylsulfonylethene, acrylic acid, and (E)-pent-3-en-2-one were used, no targeted product was observed, which can be reasonably ascribed as the electronic effect.

7



Table 4. Substrate scope for the 2-substituted 1-Indanonesa

R

R

O

O

CO2H +

[RuCl2(p-cymene)]2 R'

MnCO3, CH3CN/H2O 20 h, Ar, 150 oC

O n-C5H11 CH3

O O n-C5H11

4h: R = F, 42% 4i: R = Cl, 47% 4j: R = Br, 53% 4k: R = I , 60%

4l: R = CH3, 72% 4m: R = F, 68% 4n: R = Cl, 74% 4o: R = Br, 73% 4p: R = CF3, 59% 4q: R = OCH3, 66%

O O n-C5H11 4r 81% CH3

CH3

O O n-C5H11

R

n-C5H11

O

R

H3C

n-C5H11

O R

aReaction

O O

O

4ag: R = H, 36%c 4ah: R = CH3O, 54%c

n-C5H11 CH3

50% (4ai':4ai = 16:34)cd

O

F

n-C5H11

R

O

O

CH3

4x: R = F, 83% (75%)b 4y: R = Cl, 70% 4z: R = Br, 55%

n-C5H11

O

H3C

CH3

n-C5H11 R

n-C5H11

O

O O

4s: R = CH3, 71% 4t: R = OCH3, 62% 4u: R = F, 66% 4v: R = Cl, 66% 4w: R = Br, 68%

4aa: R = H, 52%c 4ab: R = CH3, 61%c O 4ac: R = C2H5, 61%c 4ad: R = Cl, 47%c 4ae: R =Br, 54%c O 4af: R = I, 48%c H3CO n-C5H11

O

R'

4c-4aq

4c: R = C2H5, 70% 4d: R = PhCH2, 77% 4e: R = PhCH2CH2, 73% 4f: R = Ph, 55% 4g: R = PhO, 40%

O

R

O R

4aj: R = C2H5, 58% 4ak: R = n-C6H13, 77% 4al: R = n-C7H15, 78% 4am: R = n-C8H17, 74%

4an: R = n-C9H19, 77% 4ao: R = n-C11H23, 72% 4ap: R = PhCH2CH2, 82% 4aq: R = Ph, 76%

conditions: aromatic acids (0.2 mmol), α,ß-unsaturated ketones (0.5 mmol), [RuCl2(p-cymene)]2 (5 mol%),

MnCO3 (1.0 equiv), CH3CN (0.8 mL), H2O (76 μL), 150 °C, 20 h, Ar, isolated yield. b3 mmol acid was used, 12 mL CH3CN, 1.1 mL H2O. c0.7 mmol acid was used. dDetermined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.

On the base of the observed products (3aa-3ai and 4aa-4ai), a possible catalytic cycle for this tandem cyclization is depicted in Scheme 2. Firstly, a ruthenium-catalyzed conjugate addition of C‒H bond to the first α,ß-unsaturated ketone directed by a carboxyl group takes place affording ortho-alkylated benzoic acids intermediate A, which is discussed in detail in our previous report.15 Then, the intermediate A undergoes a Dieckmann condensation reaction via enol attacking Mn(II)-activated carboxyl to deliver 2-acyl substituted 1-indanone B. Subsequently, Michael addition of the intermediate B to the second α,ß-unsaturated ketone provides the intermediate C bearing a quaternary carbon center. Finally, benefiting from chelation interactions of Mn(II) and oxygen atom, the intermediate C could proceed by two reaction routes, i.e., (1) the intramolecular Aldol condensation reaction of C to deliver spiroindanones; (2) the hydrolysis of C to afford 2-substituted 1-indanones. 8


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CO2H R

C-H activation catalyzed by Ru

CO2H

CO2H R

R

O

O Ru

conjugate addition

R' L

R'

OH O

H2O

OH

O

O

OO R'

R

R'

R'

C

C2H5

R

R' O

R' O

O

O

H2O

Mn(II)

Mn(II)

R'

R

B

R

Mn(II) OH

R

R'

O

OO

O

Mn(II)

R R'

A

O

CH3

O

H2O

O

R

R'

R'CO2H

Scheme 2. Plausible mechanism for the tandem cyclization

To

validate

the

proposed

2-methyl-6-(3-oxopentyl)benzoic

mechanism, acid

we

(5a)

and

conducted

several

reactions

utilizing

7-methyl-2-(3-oxopentyl)-2-propionyl-2,3-

dihydro-1H-inden-1-one (6a) as starting materials (Scheme 3). When 5a reacted with ethyl vinyl ketone in the absence of catalyst, 3a and 4a were obtained in 61% and 56% yield under standard reaction conditions, respectively, which clearly indicates that the conjugate addition is the key step in these two transformations and the [RuCl2(p-cymene)]2 only promotes the step of C‒H bonds activation (Scheme 3a, 3b, and See Supporting Information Table S3 and Table S5). Employing 6a as starting material, 43% yield of 3a was observed (Scheme 3c). 4a was formed in 42% yield in the presence of MnCO3 in neat water, while utilizing CH3CN as solvent failed to afford 4a (Scheme 3d and 3e). These results suggest that the Michael addition product should be the intermediate involving in the reaction, and the hydrolysis reaction occurs in the formation of 4a, which well supports the mechanism in Scheme 2. However, 3a and 4a did not be observed without Mn(II) additive (See Supporting Information Table S3-S6), which illuminates that Mn(II) additive is indispensible for the Dieckmann condensation and Aldol condensation reaction/hydrolysis.

9



CH3

CH3 CO2H

(a)

+ C2H5 5a

(b)

O C2H5

C2H5

20 h, Ar, 150 oC

O CH3 NMR yield: 61%

O

CH3

CH3

CO2H + C2H5 5a CH3

O

CH3

NMR yield: 43% CH3

O O

MnCO3, H2O C2H5

6a

O C2H5

20 h, Ar, 150 oC

O

C2H5

20 h, Ar, 150 oC

C2H5 NMR yield: 42%

O

CH3

O O

O O

MnCO3, CH3CN

C2H5 C2H5 6a

C2H5

Mn(OAc)2, CH3CN

O O

(d)

(e)

O

CH3CN/H2O

CH3

C2H5

CH3

C2H5

O O

6a

O

MnCO3, 20 h, Ar, 150 oC

NMR yield: 56%

C2H5

CH3

O

O

(c)

O

Mn(OAc)2, CH3CN

o

20 h, Ar, 150 C

O

C2H5 ND

Scheme 3. Mechanistic investigations

CONCLUSION In summary, we have developed a divergent tandem coupling and cyclization reaction for the facile synthesis of structurally diverse 1-indanones starting from commercially available aromatic acids and α,ß-unsaturated ketones. The spiroindanones and 2-substituted 1-indanones, in which four and three new bonds are formed concomitant, respectively, can be highly efficiently constructed via four steps in one pot. The chemoselectivity of this domino cyclization can be tuned by manganese additive and H2O. These two methodologies provide an efficient strategy for the construction of complex 1-indanone scaffold. Further applications of these tandem cyclization reactions for the preparation of bioactive moleculars are currently underway in our lab. EXPERIMENTAL SECTION General Information All commercials were used as received without further purification. The solvents used in reaction were dried according to the conventional methods. All work-up and purification procedures were carried out with analytical reagent solvents. The 1H NMR and 13C NMR spectra were recorded on a Bruker 400 MHz NMR or 600 MHz NMR with tetramethylsilane (TMS) as the internal standard at room temperature. Chemical shifts are given in δ relative to TMS, with the coupling constants J given in Hz. High-resolution 10


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mass spectra (HRMS) were performed on a Bruker Compass-Maxis instrument (ESI). X-ray single-crystal diffraction data were collected on a Bruker D8 Venture X-ray single crystal diffractometer. The α,ß-unsaturated ketones were prepared according to the previous report.18 2-methyl-6-(3-oxopentyl)benzoic acid (5a) was synthesized according to our previous report.16 General procedure for the synthesis of spiroindanone An oven-dried microwave vial was charged with [RuCl2(p-cymene)]2 (Ru*, 6.1 mg, 5 mol%, 0.01 mmol), Mn(OAc)2 (26.0 mg, 0.15 mmol), aromatic acids (0.2 mmol), α,ß-unsaturated ketones (0.5 mmol). After the tube was evacuated and purged with argon three times, CH3CN (0.6 mL) were added to the system by syringe. The mixture was stirred at 150 °C (oil bath temperature) for 20 h. After cooling to room temperature, the mixture was diluted with EtOAc (5 mL) and filtered through a short silica gel pad. The filter cake was further flushed with EtOAc (3 × 5 mL). The combined solution was concentrated under vacuum, and the residue was purified by a preparative TLC to afford the corresponding product. Experimental procedure for the reaction of 2,4-dimethylbenzoic acid with ethyl vinyl ketone (2a) to yield spiroindanone 3q on 6 mmol scale. An oven-dried 50 mL Schlenk tube was charged with 2,4-dimethylbenzoic acid (6 mmol, 0.9004 g), ethyl vinyl ketone (15 mmol, 1.5 mL), [RuCl2(p-cymene)]2 (Ru*, 0.3 mmol, 0.1837 g), Mn(OAc)2 (4.5 mmol, 0.7786 g), and CH3CN (18 mL). The mixture was stirred at 150 °C (oil bath temperature) in Ar for 20 h. Then, the reaction mixture was concentrated to give a crude product, which is purified by silica-gel column chromatography using hexanes/EtOAc (25/1) to yield compound 3q (1.05 g, 62%). 4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3a): Yellow oil; yield, 33.2 mg, 62%; Rf = 0.28 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.41 (t, J = 7.5 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.08 (d, J = 7.4 Hz, 1H), 3.65 (d, J = 17.0 Hz, 1H), 2.89 – 2.79 (m, 2H), 2.58 (s, 3H), 2.40 – 2.26 (m, 4H), 2.10 – 2.02 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 205.2, 197.0, 161.3, 153.8, 139.6, 134.2, 132.6, 129.4, 129.3, 123.6, 59.6, 37.6, 31.4, 28.4, 26.7, 18.4, 11.7, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H20O2Na 291.1356, found 291.1361. 4,7'-diethyl-3-methylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3b): Yellow oil; yield, 34.8 mg, 62%; Rf = 0.33 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 3.67 (d, J = 16.9 Hz, 1H), 3.09 – 2.98 (m, 2H), 2.87 – 2.79 11



Page 12 of 37

(m, 2H), 2.43 – 2.25 (m, 4H), 2.11 – 2.04 (m, 1H), 1.81 (s, 3H), 1.20 (t, J = 7.5 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 204.9, 197.1, 161.3, 153.9, 146.0, 134.4, 132.0, 129.3, 127.6,

123.7, 59.6, 37.6, 31.5, 28.4, 26.7, 24.8, 14.7, 11.7, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22O2Na 305.1512, found 305.1506. 7'-benzyl-4-ethyl-3-methylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3c): Yellow oil; yield, 39.1 mg, 57%; Rf = 0.23 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.41 (t, J = 7.6 Hz, 1H), 7.28 – 7.25 (m, 3H), 7.22 – 7.16 (m, 3H), 7.00 (d, J = 7.5 Hz, 1H), 4.44 (q, J = 15.5 Hz, 2H), 3.67 (d, J = 17.0 Hz, 1H), 2.90 – 2.73 (m, 2H), 2.43 – 2.26 (m, 4H), 2.10 – 2.03 (m, 1H), 1.81 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 205.0, 197.0, 161.3, 153.8, 142.5, 140.2, 134.4, 132.1, 129.3, 129.3, 128.8, 128.4, 126.0, 124.1, 59.8, 37.5, 36.6, 31.4, 28.4, 26.7, 11.7, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H24O2Na 367.1669, found 367.1678. 4-ethyl-3-methyl-7'-phenethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione

(3d):

Yellow

oil;

yield, 46.3 mg, 65%; Rf = 0.26 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.5 Hz, 1H), 7.29 – 7.21 (m, 5H), 7.20 – 7.13 (m, 1H), 7.05 (d, J = 7.4 Hz, 1H), 3.65 (d, J = 16.9 Hz, 1H), 3.29 (t, J = 8.1 Hz, 2H), 2.93 – 2.73 (m, 4H), 2.43 – 2.26 (m, 4H), 2.09 – 2.02 (m, 1H), 1.81 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 205.0, 197.2, 161.3, 153.9, 143.4, 141.8, 134.3, 132.3, 129.4, 128.7, 128.6, 128.2, 125.7, 124.1, 59.7, 37.6, 37.1, 34.0, 31.4, 28.5, 26.7, 11.7, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C25H26O2Na 381.1825, found 381.1838. 4-ethyl-3-methyl-7'-phenylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3e): Yellow oil; yield, 40.0 mg, 61%; Rf = 0.26 (hexanes/EtOAc = 15/1); 1H NMR (400 MHz, CDCl3) δ 7.58 (t, J = 7.5 Hz, 1H), 7.45 – 7.33 (m, 6H), 7.27 – 7.23 (m, 1H), 3.72 (d, J = 16.9 Hz, 1H), 2.91 (d, J = 16.9 Hz, 1H), 2.82 – 2.76 (m, 1H), 2.40 – 2.18 (m, 4H), 2.09 – 2.00 (m, 1H), 1.78 (s, 3H), 1.09 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 203.2, 197.1, 161.5, 154.0, 142.1, 137.9, 134.2, 131.5, 129.7, 129.3, 129.1, 127.8, 127.7, 125.2, 59.5, 37.7, 31.3, 28.4, 26.6, 11.6, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H22O2Na 353.1512, found 353.1522. 4-ethyl-3-methyl-7'-phenoxyspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3f): Yellow oil; yield, 38.9 mg, 56%; Rf = 0.16 (hexanes/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.41 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.16 (t, J = 7.4 Hz, 1H), 7.12 – 7.06 (m, 3H), 6.60 (d, J = 8.2 Hz, 1H), 3.78 (d, J = 17.0 Hz, 1H), 3.01 – 2.93 (m, 1H), 2.84 (d, J = 17.1 Hz, 1H), 2.41 – 2.29 (m, 4H), 2.17 – 2.11 (m, 1H), 1.80 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 200.8, 196.3, 161.7, 156.6, 12


Page 13 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


155.4, 136.2, 129.8, 129.0, 124.5, 124.5, 120.4, 120.0, 114.9, 59.9, 37.9, 31.5, 28.5, 26.7, 11.7, 10.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H22O3Na 369.1461, found 369.1469. 4-ethyl-7'-fluoro-3-methylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3g): Yellow soild, mp 62.1 – 62.7 oC; yield, 27.0 mg, 50%; Rf = 0.21 (hexanes/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.56 – 7.53 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 3.75 (d, J = 17.1 Hz, 1H), 2.94 – 2.83 (m, 2H), 2.39 – 2.28 (m, 4H), 2.14 – 2.07 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 200.3 (d, JC-F = 1.8 Hz), 195.9, 161.8, 159.4 (d, JC-F = 262.9 Hz), 155.1 (d, JC-F = 2.2 Hz), 136.8 (d, JC-F = 8.3 Hz), 129.0, 123.1 (d, JC-F = 12.6 Hz), 122.1 (d, JC-F = 4.1 Hz), 114.4 (d, JC-F = 19.0 Hz), 60.2, 37.9, 31.2, 28.5, 26.6, 11.6, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H17FO2Na 295.1105, found 295.1098. 7'-chloro-4-ethyl-3-methylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3h): White soild, mp 97.2 – 98.4 oC; yield, 29.5 mg, 51%; Rf = 0.23 (hexanes/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.47 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 3.74 (d, J = 17.0 Hz, 1H), 2.97 – 2.93 (m, 1H), 2.80 (d, J = 17.0 Hz, 1H), 2.38 – 2.28 (m, 4H), 2.15 – 2.10 (m, 1H), 1.80 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 200.9, 195.7, 161.9, 155.6, 135.2, 132.4, 131.0, 129.2,

128.9, 124.7, 60.2, 37.4, 31.3, 28.5, 26.6, 11.6, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H17ClO2Na 311.0809, found 311.0802. 7'-bromo-4-ethyl-3-methylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3i): Yellow soild, mp 90.1 – 92.3 oC; yield, 33.1 mg, 50%; Rf = 0.24 (hexanes/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.50 – 7.48 (m, 1H), 7.39 – 7.37 (m, 2H), 3.73 (d, J = 17.0 Hz, 1H), 2.99 – 2.90 (m, 1H), 2.78 (d, J = 17.0 Hz, 1H), 2.37 – 2.28 (m, 4H), 2.15 – 2.09 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 201.2, 195.7, 161.9, 156.0, 135.3, 132.6, 132.3, 128.9, 125.3, 120.1, 60.3, 37.3, 31.3, 28.5, 26.6, 11.6, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H1779BrO2Na 355.0304, found 355.0307; [M+Na]+ calcd for C17H1781BrO2Na 357.0283, found 357.0288. 4-ethyl-7'-iodo-3-methylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3j): Yellow soild, mp 120.4 – 121.2 oC; yield, 41.5 mg, 55%; Rf = 0.26 (hexanes/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 3.68 (d, J = 17.0 Hz, 1H), 2.96 – 2.91 (m, 1H), 2.73 (d, J = 17.0 Hz, 1H), 2.40 – 2.25 (m, 4H), 2.14 – 2.09 (m, 1H), 1.78 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 201.7, 195.7, 161.9, 156.3, 139.5, 135.3, 134.3, 128.9,

126.1, 91.2, 60.5, 37.0, 31.4, 28.4, 26.6, 11.6, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for 13



C17H17IO2Na 403.0165, found 403.0153. 4-ethyl-3-methylspiro[cyclohex[3]ene-1,2'-cyclopenta[a]naphthalene]-1',2(3'H)-dione (3k): Yellow oil; yield, 38.5 mg, 63%; Rf = 0.18 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.56 – 7.50 (m, 2H), 3.82 (d, J = 17.3 Hz, 1H), 3.00 – 2.92 (m, 2H), 2.45 – 2.34 (m, 4H), 2.20 – 2.13 (m, 1H), 1.84 (s, 3H), 1.17 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 204.8, 196.8, 161.5, 156.6, 136.1, 132.9, 129.7,

129.4, 129.0, 128.9, 128.2, 126.5, 124.0, 123.7, 60.0, 38.4, 31.5, 28.5, 26.7, 11.7, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H20O2Na 327.1356, found 327.1346. 4-ethyl-3,6',7'-trimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3l): Yellow soild, mp 82.5 – 83.1 oC; yield, 32.3 mg, 57%; Rf = 0.25 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 3.57 (d, J = 16.8 Hz, 1H), 2.87 – 2.76 (m, 2H), 2.55 (s, 3H), 2.42 – 2.30 (m, 4H), 2.28 (s, 3H), 2.09 – 2.01 (m, 1H), 1.80 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 205.6, 197.2, 161.1, 151.5, 137.8, 136.4, 136.0, 132.5, 129.2, 123.1, 59.9, 36.9, 31.4, 28.4, 26.7, 18.9, 13.6, 11.6, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22O2Na 305.1512, found 305.1519. 4-ethyl-6'-methoxy-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3m): White soild, mp 86.2 – 86.9 oC; yield, 36.0 mg, 60%; Rf = 0.25 (hexanes/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H), 3.54 (d, J = 16.5 Hz, 1H), 2.82 – 2.76 (m, 2H), 2.49 (s, 3H), 2.39 – 2.27 (m, 4H), 2.06 – 2.02 (m, 1H), 1.79 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 205.7, 197.1, 161.2, 157.2, 145.1, 133.5, 129.2, 127.6, 123.5, 117.3, 60.4, 56.3, 36.6, 31.4, 28.4, 26.7, 11.6, 10.7, 10.1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22O3Na 321.1461, found 321.1469. 4-ethyl-6'-fluoro-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3n): Yellow soild, mp 73.8 – 74.3 oC; yield, 32.4 mg, 57%; Rf = 0.26 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.16 (m, 2H), 3.57 (d, J = 16.7 Hz, 1H), 2.88 – 2.76 (m, 2H), 2.50 (d, J = 1.8 Hz, 3H), 2.41 – 2.28 (m, 4H), 2.10 – 2.03 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.8 (d, JC-F = 3.3 Hz), 196.6, 161. 5, 160.4 (d, JC-F = 242.9 Hz), 149.0 (d, JC-F = 2.3 Hz), 134.2 (d, JC-F = 5.1 Hz), 129.1, 125. 2 (d, JC-F = 18.0 Hz), 124.2 (d, JC-F = 8.2 Hz), 121.4 (d, JC-F = 24.8 Hz), 60.6, 36.9, 31.3, 28.4, 26.6, 11.6, 10.7, 9.3 (d, JC-F = 4.4 Hz); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H19FO2Na 309.1261, found 309.1262. 14


Page 14 of 37

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6'-chloro-4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3o): Yellow soild, mp 64.8 – 65.3 oC; yield, 35.7 mg, 59%; Rf = 0.26 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 3.58 (d, J = 17.0 Hz, 1H), 2.87 – 2.77 (m, 2H), 2.64 (s, 3H), 2.39 – 2.29 (m, 4H), 2.09 – 2.04 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.4, 196.5, 161.5, 152.3, 137.2, 134.7, 134.3, 133.9, 129.1, 124.4, 60.2, 36.9, 31.3, 28.5, 26.6, 14.2, 11.7, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H19ClO2Na 325.0966, found 325.0973. 6'-bromo-4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3p): White soild, mp 64.5 – 65.1 oC; yield, 36.9 mg, 53%; Rf = 0.28 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 3.57 (d, J = 17.0 Hz, 1H), 2.87 – 2.80 (m, 1H), 2.77 (d, J = 17.0 Hz, 1H), 2.67 (s, 3H), 2.40 – 2.29 (m, 4H), 2.09 – 2.04 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 204.2, 196.5, 161.5, 153.0, 139.2, 137.9, 134.0, 129.1, 125.3,

124.9, 60.1, 37.0, 31.3, 28.5, 26.6, 17.1, 11.7, 10.8; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H2079BrO2 347.0641, found 347.0648; [M+H]+ calcd for C18H2081BrO2 349.0620, found 349.0629. 4-ethyl-3,5',7'-trimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3q): White soild, mp 110.6 – 111.5 oC; yield, 35.7 mg, 63%; Rf = 0.23 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.05 (s, 1H), 6.90 (s, 1H), 3.60 (d, J = 16.9 Hz, 1H), 2.89 – 2.81 (m, 1H), 2.77 (d, J = 16.9 Hz, 1H), 2.54 (s, 3H), 2.38 – 2.29 (m, 7H), 2.08 – 2.03 (m, 1H), 1.80 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.5, 197.1, 161.3, 154.3, 145.4, 139.3, 130.7, 130.4, 129.2, 124.1, 59.8, 37.5, 31.5, 28.4, 26.7, 21.8, 18.2, 11.6, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22O2Na 305.1512, found 305.1519. 4-ethyl-5'-methoxy-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3r): Yellow soild, mp 105.4 – 105.8 oC; yield, 36.7 mg, 62%; Rf = 0.18 (hexanes/EtOAc = 15/1); 1H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.62 (s, 1H), 3.84 (s, 3H), 3.62 (d, J = 17.0 Hz, 1H), 2.94 – 2.82 (m, 1H), 2.75 (d, J = 17.0 Hz, 1H), 2.54 (s, 3H), 2.39 – 2.25 (m, 4H), 2.11 – 2.04 (m, 1H), 1.80 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 203.1, 197.1, 164.7, 161.4, 156.9, 141.6, 129.2, 126.1, 116.8, 107.1,

59.9, 55.5, 37.8, 31.6, 28.4, 26.8, 18.5, 11.7, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22O3Na 321.1461, found 321.1468. 4-ethyl-5'-fluoro-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3s): White soild, mp 97.5 – 98.1 oC; yield, 32.1 mg, 56%; Rf = 0.31 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 6.91 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 9.7 Hz, 1H), 3.65 (d, J = 17.2 Hz, 1H), 2.92 – 2.76 (m, 2H), 2.58 (s, 15



Page 16 of 37

3H), 2.40 – 2.26 (m, 4H), 2.12 – 2.04 (m, 1H), 1.80 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 203.3, 196.5, 166.5 (d, JC-F = 254.8 Hz), 161.6, 156.9 (d, J C-F = 10.7 Hz), 142.8 (d, JC-F = 10.3 Hz), 129.1, 129.1 (d, JC-F = 1.5 Hz), 117.2 (d, JC-F = 22.8 Hz), 110.3 (d, JC-F = 22.0 Hz), 60.1, 37.7 (d, JC-F = 2.2 Hz), 31.4, 28.5, 26.6, 18.4, 11.6, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H19FO2Na 309.1261, found 309.1268. 5'-chloro-4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3t): White soild, mp 128.7 – 129.2 oC; yield, 33.6 mg, 56%; Rf = 0.30 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.09 (s, 1H), 3.63 (d, J = 17.1 Hz, 1H), 2.90 – 2.75 (m, 2H), 2.55 (s, 3H), 2.39 – 2.29 (m, 4H), 2.10 – 2.03 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 203.8,

196.4, 161.6, 155.3, 141.1, 140.6, 131.2, 129.8, 129.1, 123.8, 59.9, 37.4, 31.3, 28.4, 26.6, 18.1, 11.6, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H19ClO2Na 325.0966, found 325.0973. 5'-bromo-4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3u): White soild, mp 124.5 – 124.9 oC; yield, 37.3 mg, 54%; Rf = 0.30 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.25 (s, 1H), 3.63 (d, J = 17.1 Hz, 1H), 2.89 – 2.75 (m, 2H), 2.54 (s, 3H), 2.38 – 2.29 (m, 4H), 2.10 – 2.02 (m, 1H), 1.79 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ

204.0, 196.4, 161.6, 155.4, 141.2, 132.7, 131.6, 129.6, 129.1, 126.8, 59.9, 37.4, 31.3, 28.5, 26.6, 18.0, 11.6, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H1979BrO2Na 369.0461, found 369.0469; [M+Na]+ calcd for C18H1981BrO2Na 371.0441, found 371.0449. 4-ethyl-4',7'-dimethoxy-3-methylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3v): Yellow soild, mp 122.2 – 122.9 oC; yield, 34.0 mg, 54%; Rf = 0.12 (hexanes/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.55 (d, J = 17.6 Hz, 1H), 2.90 – 2.85 (m, 1H), 2.72 (d, J = 17.6 Hz, 1H), 2.38 – 2.24 (m, 4H), 2.09 – 2.01 (m, 1H), 1.77 (s, 3H), 1.11 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 202.0, 196.5, 161.2, 152.2, 150.1, 143.5, 129.0,

124.3, 117.0, 109.8, 59.5, 55.9, 55.8, 34.3, 31.3, 28.4, 26.6, 11.6, 10.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H22O4Na 337.1410, found 337.1402. 4-ethyl-4'-fluoro-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3w): White soild, mp 92.7 – 93.2 oC; yield, 33.5 mg, 59%; Rf = 0.32 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.11 (t, J = 8.2 Hz, 1H), 7.09 – 7.05 (m, 1H), 3.63 (d, J = 17.3 Hz, 1H), 2.87 – 2.79 (m, 2H), 2.54 (s, 3H), 2.40 – 2.28 (m, 4H), 2.11 – 2.05 (m, 1H), 1.80 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 204.2, 196.4, 161.6, 158.0 (d, JC-F = 245.1 Hz), 139.1 (d, JC-F = 19.4 Hz), 135.0 (d, JC-F = 3.9 16


Page 17 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Hz), 134.7 (d, JC-F = 4.3 Hz), 131.0 (d, JC-F = 5.7 Hz), 129.2, 120.2 (d, JC-F = 19.8 Hz), 59.4, 33.1, 31.2, 28.4, 26.5, 17.6, 11.6, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H19FO2Na 309.1261, found 309.1269. 4'-chloro-4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3x): White soild, mp 117.4 – 117.9 oC; yield, 33.2 mg, 55%; Rf = 0.36 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 3.59 (d, J = 17.6 Hz, 1H), 2.87 – 2.76 (m, 2H), 2.56 (s, 3H), 2.44 – 2.31 (m, 4H), 2.11 – 2.03 (m, 1H), 1.80 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.6, 196.5, 161.5, 151.0, 138.0, 134.3, 133.7, 131.1, 129.5, 129.2, 59.5, 36.6, 31.2, 28.5, 26.6, 17.8, 11.6, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H19ClO2Na 325.0966, found 325.0974. 4'-bromo-4-ethyl-3,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3y): White soild, mp 136.2 – 137.8 oC; yield, 38.0 mg, 55%; Rf = 0.32 (hexanes/EtOAc = 25/1); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 3.54 (d, J = 17.5 Hz, 1H), 2.86 – 2.75 (m, 2H), 2.55 (s, 3H), 2.45 – 2.31 (m, 4H), 2.10 – 2.03 (m, 1H), 1.80 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.8, 196.5, 161.5, 153.0, 138.6, 136.9, 134.5, 131.4, 129.2, 118.6, 59.5, 38.7, 31.2, 28.5, 26.6, 17.9, 11.6, 10.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H1979BrO2Na 369.0461, found 369.0463; [M+Na]+ calcd for C18H1981BrO2Na 371.0441, found 371.0444. 4,7'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3z): Yellow soild, mp 83.1 – 83.7 oC; yield, 31.2 mg, 65%; Rf = 0.16 (hexanes/EtOAc = 15/1); 1H NMR (400 MHz, CDCl3) δ 7.43 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H), 5.98 (s, 1H), 3.75 (d, J = 17.0 Hz, 1H), 2.94 – 2.85 (m, 1H), 2.78 (d, J = 17.0 Hz, 1H), 2.58 (s, 3H), 2.37 – 2.25 (m, 2H), 2.19 – 2.05 (m, 1H), 2.05 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 204.6, 196.4, 163.7, 153.9, 139.7, 134.4, 132.4, 129.5, 125.4, 123.6,

59.6, 37.1, 31.9, 28.2, 24.4, 18.3; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C16H16O2Na 263.1043, found 263.1046. 4-ethyl-3-methyl-7'-(3-oxopentyl)spiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3aa): Yellow oil; yield, 33.1 mg, 49%; Rf = 0.26 (hexanes/EtOAc = 10/1); 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 6.6 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 3.60 (d, J = 17.0 Hz, 1H), 3.33 – 3.25 (m, 1H), 3.17 – 3.10 (m, 1H), 2.87 (d, J = 17.0 Hz, 1H), 2.81 – 2.60 (m, 3H), 2.42 – 2.26 (m, 6H), 2.07 – 2.00 (m, 1H), 1.79 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.7, 205.1, 197.2, 161.3, 154.0, 142.6, 134.5, 132.3, 129.3, 129.0, 124.3, 59.6, 42.8, 37.6, 35.8, 31.3, 28.4, 26.6, 26.5, 11.6, 10.7, 17



Page 18 of 37

7.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C22H26O3Na 361.1774, found 361.1773.

4-ethyl-3,5'-dimethyl-7'-(3-oxopentyl)spiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3ab): Yellow oil; yield, 39.6 mg, 56%; Rf = 0.12 (hexanes/EtOAc = 20/1); 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.95 (s, 1H), 3.55 (d, J = 17.0 Hz, 1H), 3.27 – 3.20 (m, 1H), 3.14 – 3.06 (m, 1H), 2.81 (d, J = 16.9 Hz, 1H), 2.78 – 2.60 (m, 3H), 2.44 – 2.29 (m, 9H), 2.06 – 1.99 (m, 1H), 1.79 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 210.9, 204.5, 197.4, 161.3, 154.6, 145.8, 142.4,

130.3, 130.2, 129.4, 124.8, 59.8, 42.9, 37.5, 35.8, 31.4, 28.4, 26.7, 26.5, 21.9, 11.7, 10.7, 7.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H28O3Na 375.1931, found 375.1931. 4,5'-diethyl-3-methyl-7'-(3-oxopentyl)spiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3ac): Yellow oil; yield, 41.9 mg, 57%; Rf = 0.14 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.09 (s, 1H), 6.96 (s, 1H), 3.56 (d, J = 16.9 Hz, 1H), 3.28 – 3.23 (m, 1H), 3.13 – 3.08 (m, 1H), 2.83 (d, J = 16.9 Hz, 1H), 2.78 – 2.62 (m, 5H), 2.44 – 2.27 (m, 6H), 2.06 – 2.00 (m, 1H), 1.79 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.9, 204.5, 197.4, 161.3, 154.6, 152.0, 142.4, 130.3, 129.3, 129.2, 123.5, 59.7, 42.9, 37.5, 35.8, 31.4, 29.1, 28.4, 26.7, 26.6, 15.1, 11.6, 10.7, 7.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H30O3Na 389.2087, found 389.2087. 4-ethyl-5'-methoxy-3-methyl-7'-(3-oxopentyl)spiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione(3ad): Yellow oil; yield, 38.1 mg, 52%; Rf = 0.25 (hexanes/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3) δ 6.71 (s, 1H), 6.67 (s, 1H), 3.83 (s, 3H), 3.57 (d, J = 17.0 Hz, 1H), 3.28 – 3.19 (m, 1H), 3.14 – 3.05 (m, 1H), 2.84 – 2.62 (m, 4H), 2.43 – 2.24 (m, 6H), 2.07 – 2.00 (m, 1H), 1.79 (s, 3H), 1.11 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 210.7, 202.9, 197.3, 164.9, 161.3, 157.2, 144.6, 129.3,

125.7, 116.4, 107.8, 59.8, 55.5, 42.6, 37.8, 35.7, 31.5, 28.4, 26.7, 26.6, 11.6, 10.7, 7.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H28O4Na 391.1880, found 391.1877. 5'-ethoxy-4-ethyl-3-methyl-7'-(3-oxopentyl)spiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione

(3ae):

Yellow oil; yield, 41.4 mg, 54%; Rf = 0.30 (hexanes/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3) δ 6.69 (s, 1H), 6.67 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.57 (d, J = 17.0 Hz, 1H), 3.28 – 3.20 (m, 1H), 3.14 – 3.05 (m, 1H), 2.85 – 2.61 (m, 4H), 2.45 – 2.24 (m, 6H), 2.08 – 2.01 (m, 1H), 1.80 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H), 1.01 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.8, 202.9, 197.4, 164.3, 161.4, 157.2, 144.6, 129.4, 125.5, 116.8, 108.3, 63.9, 59.8, 42.7, 37.8, 35.8, 31.5, 28.4, 26.7, 26.7, 14.6, 11.6, 10.7, 7.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H30O4Na 405.2036, found 405.2039. 4-ethyl-6'-methoxy-3-methyl-7'-(3-oxopentyl)spiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3af): 18


Page 19 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Yellow oil; yield, 25.7 mg, 35%; Rf = 0.31 (hexanes/EtOAc = 5/1); 1H NMR (600 MHz, CDCl3) δ 7.12 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 3.85 (s, 3H), 3.43 (d, J = 17.4 Hz, 1H), 3.26 – 3.20 (m, 1H), 3.11 – 3.05 (m, 1H), 2.83 (d, J = 17.4 Hz, 1H), 2.75 – 2.62 (m, 3H), 2.46 – 2.29 (m, 6H), 2.03 – 1.98 (m, 1H), 1.79 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.2, 205.6, 197.5, 161.1, 155.1, 142.5, 133.6, 133.4, 130.3, 129.3, 114.9, 59.3, 55.4, 43.2, 35.8, 34.1, 31.0, 28.4, 26.6, 25.8, 11.6, 10.6, 7.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H28O4Na 391.1880, found 391.1871.

4-ethyl-4',6'-dimethoxy-3-methyl-7'-(3-oxopentyl)spiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3ag): Orange oil; yield, 43.1 mg, 54%; Rf = 0.20 (hexanes/EtOAc = 5/1); 1H NMR (600 MHz, CDCl3) δ 6.61 (s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.33 (d, J = 16.9 Hz, 1H), 3.25 – 3.17 (m, 2H), 2.75 (d, J = 16.9 Hz, 1H), 2.69 – 2.66 (m, 1H), 2.55 – 2.40 (m, 5H), 2.37 – 2.26 (m, 3H), 2.00 – 1.94 (m, 1H), 1.77 (s, 3H), 1.10 (t, J = 7.6 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 211.5, 205.7, 197.5, 161.0, 158.1, 155.2, 134.1, 133.5, 129.2, 120.9, 100.5, 59.6, 56.5, 55.5, 42.4, 35.3, 33.2, 31.0, 28.4, 26.6, 18.5, 11.6, 10.6, 7.7;

HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H30O5Na 421.1985, found 421.1975. 4-ethyl-3,6'-dimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3ah): Yellow oil; yield, 12.5 mg, 23%; Rf = 0.32 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.50 (s, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 3.64 (d, J = 16.8 Hz, 1H), 2.87 – 2.79 (m, 2H), 2.38 (s, 3H), 2.36 – 2.30 (m, 4H), 2.09 – 2.04 (m, 1H), 1.79 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 204.4, 196.7,

161.3, 150.4, 137.5, 136.2, 135.4, 129.2, 126.0, 124.3, 60.0, 37.6, 31.3, 28.4, 26.7, 21.0, 11.6, 10.8; HRMS

(ESI-TOF) m/z: [M+Na]+ calcd for C18H20O2Na 291.1356, found 291.1352. 4-ethyl-3,4',6'-trimethylspiro[cyclohex[3]ene-1,2'-indene]-1',2(3'H)-dione (3ai): Yellow oil; yield, 13.5 mg, 24%; Rf = 0.49 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.27 (s, 1H), 7.15 (s, 1H), 3.43 (d, J = 16.8 Hz, 1H), 2.78 – 2.71 (m, 1H), 2.66 (d, J = 16.8 Hz, 1H), 2.33 – 2.24 (m, 7H), 2.22 (s, 3H), 2.01 – 1.97 (m, 1H), 1.72 (s, 3H), 1.06 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 204.8, 196.9, 161.3, 149.4, 137.7, 136.7, 135.2, 135.1, 129.2, 121.7, 59.9, 36.4, 31.3, 28.4, 26.7, 20.9, 17.6, 11.6, 10.7; HRMS (ESI-TOF)

m/z: [M+Na]+ calcd for C19H22O2Na 305.1512, found 305.1507. General procedure for the synthesis of 2-substituted 1-indanone An oven-dried microwave vial was charged with [RuCl2(p-cymene)]2 (Ru*, 6.1 mg, 5 mol%, 0.01 mmol), MnCO3 (23.0 mg, 0.2 mmol), aromatic acids (0.2 mmol), α,ß-unsaturated ketones (0.5 mmol). After the tube was evacuated and purged with argon three times, the deionized water (76 μL) and CH3CN (0.8 mL) 19



were added to the system by syringe. The mixture was stirred at 150 °C (oil bath temperature) for 20 h. After cooling to room temperature, the mixture was diluted with EtOAc (5 mL) and filtered through a short silica gel pad. The filter cake was further flushed with EtOAc (3 × 5 mL). The combined solution was concentrated under vacuum, and the residue was purified by a preparative TLC to afford the corresponding product. Experimental procedure for the reaction of 5-fluoro-2-methylbenzoic acid with oct-1-en-3-one (2b) to yield 2-substituted 1-indanone 4x on 3 mmol scale. An oven-dried 50 mL Schlenk tube was charged with 5-fluoro-2-methylbenzoic acid (3 mmol, 0.4621

g), oct-1-en-3-one (1.1 mL, 7.5 mmol), [RuCl2(p-cymene)]2 (Ru*, 0.15 mmol, 0.0919 g), H2O (1.1 mL), CH3CN (12 mL). The mixture was stirred at 150 °C (oil bath temperature) in Ar for 20 h. Then, the reaction mixture was concentrated to give a crude product which was purified by silica-gel column chromatography using hexanes/EtOAc (25/1) to yield compound 4x (0.65 g, 75%). 7-methyl-2-(3-oxopentyl)-2,3-dihydro-1H-inden-1-one (4a): Yellow solid, mp 62.5 – 63.2 oC; yield, 12.4 mg, 54%; Rf = 0.20 (hexanes/EtOAc = 15/1); 1H NMR (600 MHz, CDCl3) δ 7.38 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 3.25 (dd, J = 17.0, 8.1 Hz, 1H), 2.69 (dd, J = 17.0, 4.2 Hz, 1H), 2.62 – 2.55 (m, 6H), 2.46 – 2.40 (m, 2H), 2.07 – 2.01 (m, 1H), 1.87 – 1.80 (m, 1H), 1.03 (t, J = 7.4 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 211.0, 209.2, 154.0, 138.9, 134.0, 133.9, 129.2, 123.7,

46.4, 39.5, 35.8, 32.5, 25.5, 18.2, 7.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H18O2Na 253.1199, found 253.1208. 7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4b): Yellow solid, mp 32.5 – 33.0 oC; yield, 39.7 mg, 73%; Rf = 0.16 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.41 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 3.27 (dd, J = 17.0, 8.0 Hz, 1H), 2.71 (dd, J = 17.0, 4.2 Hz, 1H), 2.63 – 2.58 (m, 6H), 2.41 (t, J = 7.5 Hz, 2H), 2.08 – 2.02 (m, 1H), 1.88 – 1.82 (m, 1H), 1.59 – 1.54 (m, 2H), 1.31 – 1.22 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.8, 209.2, 154.0, 138.9, 134.0, 134.0, 129.2, 123.7, 46.4, 42.8, 39.9, 32.6, 31.4, 25.5, 23.5, 22.4, 18.3, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H24O2Na 295.1669, found 295.1679. 7-ethyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4c): Yellow oil; yield, 40.2 mg, 70%; Rf = 0.24 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.44 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 3.28 (dd, J = 17.0, 8.0 Hz, 1H), 3.11 – 3.00 (m, 2H), 2.71 (dd, J = 17.0, 4.2 Hz, 20


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1H), 2.64 – 2.57 (m, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.08 – 2.02 (m, 1H), 1.88 – 1.82 (m, 1H), 1.59 – 1.54 (m, 2H), 1.33 – 1.23 (m, 4H), 1.20 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.7, 208.9, 154.2, 145.4, 134.3, 133.3, 127.5, 123.8, 46.4, 42.8, 39.9, 32.6, 31.4, 25.6, 24.8, 23.5, 22.4, 14.9, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H26O2Na 309.1825, found 309.1815. 7-benzyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4d): Yellow oil; yield, 53.6 mg, 77%; Rf = 0.19 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.43 (t, J = 7.5 Hz, 1H), 7.28 – 7.21 (m, 5H), 7.17 (t, J = 7.0 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 4.51 – 4.40 (m, 2H), 3.28 (dd, J = 17.1, 8.1 Hz, 1H), 2.73 (dd, J = 17.1, 4.1 Hz, 1H), 2.65 – 2.61 (m, 1H), 2.59 (t, J = 7.6 Hz, 2H), 2.41 (t, J = 7.5 Hz, 2H), 2.10 – 2.03 (m, 1H), 1.90 – 1.83 (m, 1H), 1.60 – 1.54 (m, 2H), 1.34 – 1.23 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.7, 208.8, 154.3, 141.8, 140.3, 134.3, 133.4, 129.1, 128.8, 128.3, 126.0, 124.3, 46.5, 42.8, 39.9, 36.6, 32.5, 31.3, 25.5, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H28O2Na 371.1982, found 371.1973. 2-(3-oxooctyl)-7-phenethyl-2,3-dihydro-1H-inden-1-one (4e): Yellow oil; yield, 52.7 mg, 73%; Rf = 0.21 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.42 (t, J = 7.5 Hz, 1H), 7.29 – 7.24 (m, 5H), 7.19 – 7.16 (m, 1H), 7.06 (d, J = 7.4 Hz, 1H), 3.36 – 3.26 (m, 3H), 2.86 (t, J = 8.2 Hz, 2H), 2.74 (dd, J = 17.0, 4.2 Hz, 1H), 2.65 – 2.61 (m, 3H), 2.43 (t, J = 7.3 Hz, 2H), 2.12 – 2.06 (m, 1H), 1.90 – 1.84 (m, 1H), 1.61 – 1.55 (m, 2H), 1.33 – 1.25 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.7, 208.8, 154.4, 142.8, 141.8, 134.1, 133.5, 128.6, 128.6, 128.2, 125.8, 124.2, 46.5, 42.8, 40.0, 37.3, 34.1, 32.7, 31.4, 25.5, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C25H30O2Na 385.2138, found 385.2130. 2-(3-oxooctyl)-7-phenyl-2,3-dihydro-1H-inden-1-one (4f): Yellow oil; yield, 36.9 mg, 55%; Rf = 0.32 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.58 (t, J = 7.5 Hz, 1H), 7.44 – 7.36 (m, 6H), 7.26 – 7.24 (m, 1H), 3.36 (dd, J = 17.0, 8.2 Hz, 1H), 2.79 (dd, J = 17.0, 4.4 Hz, 1H), 2.68 – 2.59 (m, 3H), 2.39 (t, J = 7.5 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.91 – 1.85 (m, 1H), 1.58 – 1.53 (m, 2H), 1.31 – 1.23 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.8, 207.0, 154.4, 141.6, 137.9, 134.0, 132.6, 129.5, 129.2, 127.8, 127.7, 125.4, 46.5, 42.7, 39.9, 32.6, 31.4, 25.3, 23.4, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H26O2Na 357.1825, found 357.1815. 2-(3-oxooctyl)-7-phenoxy-2,3-dihydro-1H-inden-1-one (4g): Yellow solid, mp 39.5 – 39.7 oC; yield, 28.0 mg, 40%; Rf = 0.19 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.41 (t, J = 7.8 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 7.10 – 7.05 (m, 3H), 6.62 (d, J = 8.1 Hz, 1H), 3.33 (dd, J = 21



Page 22 of 37

17.2, 8.1 Hz, 1H), 2.77 (dd, J = 17.2, 4.1 Hz, 1H), 2.71 – 2.60 (m, 3H), 2.41 (td, J = 7.2, 1.6 Hz, 2H), 2.07 – 2.00 (m, 1H), 1.95 – 1.88 (m, 1H), 1.59 – 1.54 (m, 2H), 1.31 – 1.24 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 210.9, 205.2, 156.0, 155.7, 155.6, 136.0, 129.8, 126.1, 124.4, 120.3,

120.2, 115.1, 46.5, 42.8, 39.8, 32.9, 31.4, 25.7, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H26O3Na 373.1774, found 373.1761. 7-fluoro-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4h): Yellow oil; yield, 23.2 mg, 42%; Rf = 0.23 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.56 – 7.52 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 3.34 (dd, J = 17.3, 8.0 Hz, 1H), 2.78 (dd, J = 17.3, 4.1 Hz, 1H), 2.71 – 2.57 (m, 3H), 2.41 (td, J = 7.1, 1.1 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.93 – 1.87 (m, 1H), 1.59 – 1.53 (m, 2H), 1.31 – 1.24 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.6, 204.5, 159.0 (d, JC-F = 262.2 Hz), 155.4 (d, JC-F = 2.2 Hz), 136.6 (d, JC-F = 8.3 Hz), 124.4 (d, JC-F = 12.8 Hz), 122.3 (d, JC-F = 4.1 Hz), 114.3 (d, JC-F = 19.1 Hz), 46.6, 42.9, 39.7, 33.1, 31.4, 25.4, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H21FO2Na 299.1418, found 299.1408. 7-chloro-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4i): Yellow oil; yield, 27.7 mg, 47%; Rf = 0.27 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.46 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 3.30 (dd, J = 17.1, 8.0 Hz, 1H), 2.73 (dd, J = 17.1, 4.2 Hz, 1H), 2.75 – 2.59 (m, 3H), 2.44 – 2.39 (m, 2H), 2.05 – 1.99 (m, 1H), 1.93 – 1.87 (m, 1H), 1.59 – 1.53 (m, 2H), 1.31 – 1.24 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.6, 205.2, 155.6, 135.0, 132.4, 131.9, 129.1, 124.9, 46.7, 42.8, 39.7, 32.5, 31.4, 25.4, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H21ClO2Na 315.1122, found 315.1117. 7-bromo-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4j): Yellow oil; yield, 35.4 mg, 53%; Rf = 0.27 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.51 – 7.48 (m, 1H), 7.40 – 7.36 (m, 2H), 3.29 (dd, J = 16.9, 7.8 Hz, 1H), 2.75 – 2.60 (m, 4H), 2.43 – 2.39 (m, 2H), 2.05 – 1.99 (m, 1H), 1.93 – 1.87 (m, 1H), 1.59 – 1.53 (m, 2H), 1.31 – 1.23 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ

210.6, 205.4, 156.0, 135.1, 133.8, 132.5, 125.5, 119.6, 46.8, 42.8, 39.7, 32.3, 31.4, 25.4, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H2179BrO2Na 359.0617, found 359.0608; [M+Na]+ calcd for C17H2181BrO2Na 361.0597, found 361.0590. 7-iodo-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4k): Yellow oil; yield, 46.4 mg, 60%; Rf = 0.27 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 3.24 (dd, J = 18.0, 9.1 Hz, 1H), 2.72 – 2.64 (m, 4H), 2.43 – 2.40 (m, 2H), 2.05 – 22


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1.99 (m, 1H), 1.94 – 1.88 (m, 1H), 1.59 – 1.54 (m, 2H), 1.33 – 1.22 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 210.6, 205.9, 156.2, 139.3, 135.9, 135.1, 126.3, 90.7, 47.0, 42.8, 39.8,

32.0, 31.4, 25.4, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H21IO2Na 407.0478, found 407.0467. 6,7-dimethyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4l): Yellow solid, mp 48.4 – 49.0 oC; yield, 41.0 mg, 72%; Rf = 0.17 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.31 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 3.21 (dd, J = 16.7, 7.9 Hz, 1H), 2.64 (dd, J = 16.8, 4.1 Hz, 1H), 2.59 (t, J = 7.4 Hz, 3H), 2.56 (s, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 2.08 – 2.02 (m, 1H), 1.87 – 1.81 (m, 1H), 1.59 – 1.53 (m, 2H), 1.32 – 1.22 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 210.8,

209.5, 151.8, 137.3, 136.2, 135.8, 133.8, 123.2, 46.9, 42.8, 39.9, 31.9, 31.4, 25.6, 23.5, 22.4, 18.9, 13.8, 13.6; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H26O2Na 309.1825, found 309.1815. 6-fluoro-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4m): Yellow solid, mp 39.8 – 41.2 oC; yield, 39.7 mg, 68%; Rf = 0.17 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.22 – 7.16 (m, 2H), 3.22 (dd, J = 17.6, 8.7 Hz, 1H), 2.68 – 2.63 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.52 (d, J = 1.7 Hz, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.08 – 2.01 (m, 1H), 1.88 – 1.82 (m, 1H), 1.59 – 1.53 (m, 2H), 1.33 – 1.22 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 210.6, 208.7, 160.3 (d, JC-F = 243.1 Hz),

149.2, 135.5 (d, JC-F = 4.9 Hz), 124.7 (d, JC-F = 17.7 Hz), 124.3 (d, JC-F = 8.2 Hz), 121.2 (d, JC-F = 24.7 Hz), 47.4, 42.8, 39.8, 31.9, 31.4, 25.4, 23.5, 22.4, 13.8, 9.2 (d, JC-F = 4.4 Hz); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H23FO2Na 313.1574, found 313.1567. 6-chloro-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4n): Yellow solid, mp 63.2 – 64.1 oC; yield, 45.2 mg, 74%; Rf = 0.17 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 3.22 (dd, J = 17.8, 8.7 Hz, 1H), 2.69 – 2.62 (m, 5H), 2.60 (t, J = 6.9 Hz, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.07 – 2.01 (m, 1H), 1.87 – 1.81 (m, 1H), 1.58 – 1.53 (m, 2H), 1.30 – 1.23 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 210.5, 208.2, 152.4, 136.7, 135.2, 134.5,

134.1, 124.6, 47.0, 42.8, 39.8, 31.9, 31.3, 25.4, 23.5, 22.4, 14.0, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H23ClO2Na 329.1279, found 329.1276. 6-bromo-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4o): Yellow solid, mp 63.9 – 64.6 oC; yield, 51.0 mg, 73%; Rf = 0.17 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 3.21 (dd, J = 18.0, 8.9 Hz, 1H), 2.69 (s, 3H), 2.67 – 2.56 (m, 4H), 2.41 (t, J = 7.5 Hz, 2H), 2.08 – 2.02 (m, 1H), 1.89 – 1.82 (m, 1H), 1.59 – 1.54 (m, 2H), 1.33 – 1.22 (m, 4H), 0.88 (t, J 23



Page 24 of 37

= 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.5, 208.0, 153.1, 138.7, 137.7, 135.3, 125.1, 125.0, 46.9, 42.8, 39.8, 32.0, 31.4, 25.4, 23.5, 22.4, 17.0, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H2379BrO2Na 373.0774, found 373.0766; [M+Na]+ calcd for C18H2381BrO2Na 375.0754, found 375.0747. 7-methyl-2-(3-oxooctyl)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (4p): Yellow solid, mp 60.5 – 61.8 oC; yield, 39.9 mg, 59%; Rf = 0.20 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 3.30 (dd, J = 17.4, 8.1 Hz, 1H), 2.80 – 2.71 (m, 4H), 2.70 – 2.58 (m, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.08 – 2.03 (m, 1H), 1.89 – 1.83 (m, 1H), 1.60 – 1.54 (m, 2H), 1.31 – 1.24 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.5, 208.2, 157.1, 139.0 (d, JC-F = 1.2 Hz), 135.1, 131.1 (q, JC-F = 5.4 Hz), 128.9 (q, JC-F = 29.4 Hz), 124.2 (q, JC-F = 272.5 Hz), 123.8, 46.9, 42.8, 39.8, 32.3, 31.4, 25.4, 23.5, 22.4, 13.8, 13.6 (d, JC-F = 1.5 Hz); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H23F3O2Na 363.1542, found 363.1547. 6-methoxy-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4q): Yellow solid, mp 49.3 – 51.6 oC; yield, 39.9 mg, 66%; Rf = 0.31 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.18 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H), 3.19 (dd, J = 17.4, 8.9 Hz, 1H), 2.65 – 2.58 (m, 4H), 2.50 (s, 3H), 2.40 (t, J = 7.3 Hz, 2H), 2.07 – 2.02 (m, 1H), 1.87 – 1.81 (m, 1H), 1.58 – 1.53 (m, 2H), 1.31 – 1.23 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.8, 209.6, 156.9, 145.3, 134.7, 126.9, 123.7, 116.9, 56.2, 47.4, 42.8, 39.9, 31.6, 31.4, 25.6, 23.5, 22.4, 13.8, 10.0; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H26O3Na 325.1774, found 325.1766. 2-(3-oxooctyl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one (4r): Yellow solid, mp 40.2 – 40.8 oC; yield, 49.7 mg, 81%; Rf = 0.12 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 9.11 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 3.39 (dd, J = 17.4, 7.5 Hz, 1H), 2.84 (dd, J = 17.4, 3.4 Hz, 1H), 2.77 – 2.72 (m, 1H), 2.69 – 2.60 (m, 2H), 2.42 (td, J = 7.2, 1.2 Hz, 2H), 2.16 – 2.10 (m, 1H), 1.97 – 1.90 (m, 1H), 1.60 – 1.55 (m, 2H), 1.32 – 1.23 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 210.7,

208.8, 156.6, 135.8, 132.6, 130.4, 129.4, 128.8, 128.1, 126.5, 123.9, 123.8, 46.5, 42.8, 39.8, 33.3, 31.3, 25.6, 23.5, 22.4, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H24O2Na 331.1669, found 331.1670. 5,7-dimethyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4s): Yellow solid, mp 32.7 – 33.2 oC; yield, 40.4 mg, 71%; Rf = 0.16 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.03 (s, 1H), 6.89 (s, 1H), 3.21 (dd, J = 17.0, 8.0 Hz, 1H), 2.65 (dd, J = 17.0, 4.1 Hz, 1H), 2.60 (t, J = 7.6 Hz, 3H), 2.56 (s, 3H), 2.40 24


Page 25 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(t, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.06 – 2.00 (m, 1H), 1.87 – 1.81 (m, 1H), 1.59 – 1.53 (m, 2H), 1.32 – 1.22 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.8, 208.6, 154.6, 145.1, 138.6, 131.8, 130.4, 124.2, 46.5, 42.8, 40.0, 32.4, 31.4, 25.6, 23.5, 22.4, 21.7, 18.1, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H26O2Na 309.1825, found 309.1817. 5-methoxy-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4t): Yellow oil; yield, 37.5 mg, 62%; Rf = 0.25 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 6.68 (s, 1H), 6.62 (s, 1H), 3.84 (s, 3H), 3.22 (dd, J = 17.1, 8.0 Hz, 1H), 2.66 (dd, J = 17.1, 4.0 Hz, 1H), 2.61 (t, J = 7.5 Hz, 3H), 2.58 (s, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.88 – 1.82 (m, 1H), 1.59 – 1.54 (m, 2H), 1.33 – 1.22 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.9, 207.3, 164.6 157.1, 140.9, 127.6, 116.5, 107.3, 55.4, 46.6, 42.8, 40.0, 32.8, 31.4, 25.8, 23.5, 22.4, 18.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H26O3Na 325.1774, found 325.1769. 5-fluoro-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4u): Yellow solid, mp 49.2 – 51.2 oC; yield, 38.2 mg, 66%; Rf = 0.16 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 6.88 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 9.6 Hz, 1H), 3.25 (dd, J = 17.3, 8.0 Hz, 1H), 2.69 (dd, J = 17.3, 4.1 Hz, 1H), 2.64 – 2.57 (m, 6H), 2.40 (t, J = 7.5 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.87 – 1.81 (m, 1H), 1.58 – 1.52 (m, 2H), 1.32 – 1.21 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.6, 207.3, 166.4 (d, JC-F = 254.2 Hz), 157.0 (d, JC-F = 10.4 Hz), 142.1 (d, JC-F = 10.2 Hz), 130.5 (d, JC-F = 1.4 Hz), 116.9 (d, JC-F = 22.7 Hz), 110.3 (d, JC-F = 21.7 Hz), 46.7, 42.8, 39.8, 32.7 (d, JC-F = 2.1 Hz), 31.4, 25.5, 23.5, 22.4, 18.3, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H23FO2Na 313.1574, found 313.1573. 5-chloro-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4v): Yellow solid, mp 40.1 – 40.9 oC; yield, 40.4 mg, 66%; Rf = 0.17 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.21 (s, 1H), 7.07 (s, 1H), 3.24 (dd, J = 17.2, 8.0 Hz, 1H), 2.68 (dd, J = 17.2, 4.2 Hz, 1H), 2.60 (t, J = 7.0 Hz, 3H), 2.57 (s, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.87 – 1.81 (m, 1H), 1.58 – 1.53 (m, 2H), 1.31 – 1.23 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.5, 207.8, 155.5, 140.5, 140.3, 132.5, 129.6, 123.9, 46.6, 42.8, 39.8, 32.4, 31.3, 25.5, 23.5, 22.4, 18.0, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H23ClO2Na 329.1279, found 329.1274. 5-bromo-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4w): Yellow solid, mp 43.6 – 44.2 oC; yield, 47.5 mg, 68%; Rf = 0.17 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.39 (s, 1H), 7.24 (s, 1H), 3.25 (dd, J = 17.2, 8.1 Hz, 1H), 2.69 (dd, J = 17.3, 4.1 Hz, 1H), 2.60 (t, J = 7.3 Hz, 3H), 2.56 (s, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.87 – 1.81 (m, 1H), 1.58 – 1.53 (m, 2H), 1.31 – 1.24 (m, 25



4H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.5, 208.0, 155.6, 140.6, 132.9, 132.4, 129.2, 127.0, 46.5, 42.8, 39.8, 32.4, 31.4, 25.4, 23.5, 22.4, 18.0 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H2379BrO2Na 373.0774, found 373.0770; [M+Na]+ calcd for C18H2381BrO2Na 375.0754, found 375.0751. 4-fluoro-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4x): Yellow oil; yield, 48.2 mg, 83%; Rf = 0.28 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.09 (t, J = 8.2 Hz, 1H), 7.06 – 7.04 (m, 1H), 3.28 (dd, J = 17.3, 8.0 Hz, 1H), 2.67 (dd, J = 17.3, 4.1 Hz, 1H), 2.61 (t, J = 7.2 Hz, 3H), 2.54 (s, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.08 – 2.02 (m, 1H), 1.88 – 1.81 (m, 1H), 1.60 – 1.53 (m, 2H), 1.31 – 1.22 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H);

13C{1H}


139.3 (d, JC-F = 19.6 Hz), 135.9 (d, JC-F = 4.3 Hz), 134.4 (d, JC-F = 3.9 Hz), 130.8 (d, JC-F = 5.7 Hz), 120.0 (d, JC-F = 19.8 Hz), 46.2, 42.8, 39.7, 31.3, 28.0, 25.4, 23.4, 22.4, 17.4, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H23FO2Na 313.1574, found 313.1563. 4-chloro-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4y): Yellow oil; yield, 43.0 mg, 70%; Rf = 0.30 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 3.26 (dd, J = 17.2, 7.7 Hz, 1H), 2.69 – 2.60 (m, 4H), 2.57 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.10 – 2.04 (m, 1H), 1.88 – 1.82 (m, 1H), 1.59 – 1.54 (m, 2H), 1.31 – 1.23 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 210.4, 208.3, 151.3, 137.4, 135.6, 133.5, 130.8, 129.6, 46.2, 42.8, 39.8,

31.6, 31.4, 25.4, 23.5, 22.4, 17.7, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H23ClO2Na 329.1279, found 329.1268. 4-bromo-7-methyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4z): Yellow oil; yield, 38.2 mg, 55%; Rf = 0.30 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 3.22 (dd, J = 18.4, 8.9 Hz, 1H), 2.67 – 2.60 (m, 4H), 2.56 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.10 – 2.04 (m, 1H), 1.88 – 1.82 (m, 1H), 1.60 – 1.54 (m, 2H), 1.32 – 1.24 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 210.4, 208.5, 153.3, 138.1, 136.7, 135.8, 131.2, 118.8, 46.3, 42.8, 39.8,

33.7, 31.4, 25.4, 23.5, 22.4, 17.8, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H2379BrO2Na 373.0774, found 373.0779; [M+Na]+ calcd for C18H2381BrO2Na 375.0754, found 375.0761. 1,1'-(3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4aa): Yellow oil; yield, 40.0 mg, 52%; Rf = 0.36 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.44 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 3.32 – 3.20 (m, 3H), 2.75 – 2.70 (m, 3H), 2.64 – 2.59 (m, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 2.10 – 2.04 (m, 1H), 1.88 – 1.82 (m, 1H), 1.62 – 1.52 (m, 4H), 1.31 – 1.23 (m, 8H), 26


Page 26 of 37

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0.90 – 0.85 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.7, 210.4, 208.9, 154.5, 142.1, 134.4, 133.6, 128.9, 124.5, 46.5, 43.3, 42.8, 42.7, 40.0, 32.8, 31.4, 31.4, 26.4, 25.6, 23.5, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z:

[M+Na]+ calcd for C25H36O3Na 407.2557, found 407.2553. 1,1'-(6-methyl-3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4ab): Yellow soild, mp 39.2 – 40.3 oC; yield, 48.4 mg, 61% (isolated yield); Rf = 0.12 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.05 (s, 1H), 6.94 (s, 1H), 3.24 – 3.13 (m, 3H), 2.70 – 2.64 (m, 3H), 2.61 – 2.56 (m, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.39 – 2.34 (m, 5H), 2.07 – 2.01 (m, 1H), 1.85 – 1.79 (m, 1H), 1.58 – 1.50 (m, 4H), 1.30 – 1.20 (m, 8H), 0.88 – 0.84 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.7, 210.5, 208.2, 155.0, 145.5, 141.8, 131.3, 130.0, 124.9, 46.6, 43.2, 42.8, 42.6, 40.0, 32.5, 31.4, 31.3, 26.4, 25.6, 23.5, 23.4, 22.4, 21.8, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C26H38O3Na 421.2713, found 421.2712. 1,1'-(6-ethyl-3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4ac): Yellow oil; yield, 50.3 mg, 61%; Rf = 0.17 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.07 (s, 1H), 6.95 (s, 1H), 3.26 – 3.14 (m, 3H), 2.68 (t, J = 7.5 Hz, 2H), 2.66 – 2.62 (m, 2H), 2.61 – 2.56 (m, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.36 (t, J = 7.5 Hz, 2H), 2.07 – 2.01(m, 1H), 1.85 – 1.79 (m, 1H), 1.58 – 1.49 (m, 4H), 1.31 – 1.18 (m, 12H), 0.87 – 0.83 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.7, 210.5, 208.2, 155.1, 151.8, 141.9, 131.5, 128.9, 123.6, 46.6, 43.3, 42.7, 42.6, 40.0, 32.6, 31.3, 31.3, 29.1, 26.5, 25.6, 23.4, 23.4, 22.4, 15.2, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C27H40O3Na 435.2870, found 435.2869. 1,1'-(6-chloro-3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4ad): Yellow soild, mp 44.6 – 45.8 oC; yield, 39.2 mg, 47%; Rf = 0.14 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.25 (s, 1H), 7.15 (s, 1H), 3.27 (dd, J = 17.2, 8.0 Hz, 1H), 3.24 – 3.16 (m, 2H), 2.74 – 2.68 (m, 3H), 2.66 – 2.60 (m, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 2.08 – 2.02 (m, 1H), 1.88 – 1.81 (m, 1H), 1.60 – 1.53 (m, 4H), 1.34 – 1.20 (m, 8H), 0.88 (q, J = 7.3 Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.5, 209.9, 207.4, 156.0, 143.7, 140.7, 132.1, 129.3, 124.5, 46.7, 42.9, 42.8, 42.7, 39.8, 32.6, 31.4, 31.4, 26.0, 25.5, 23.5, 23.5, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C25H35ClO3Na 441.2167, found 441.2166. 1,1'-(6-bromo-3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4ae): Yellow oil; yield, 50.1 mg, 54%; Rf = 0.15 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.42 (s, 1H), 7.30 (s, 1H), 3.26 (dd, J = 17.3, 8.1 Hz, 1H), 3.23 – 3.14 (m, 2H), 2.72 – 2.66 (m, 3H), 2.63 – 2.57 (m, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.37 (t, J = 7.5 Hz, 2H), 2.07 – 2.01 (m, 1H), 1.86 – 1.80 (m, 1H), 1.58 – 1.51 (m, 4H), 1.30 – 1.21 (m, 8H), 0.86 (q, J = 7.4 Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.5, 209.8, 207.6, 156.0, 143.8, 132.4, 27



Page 28 of 37

132.1, 129.6, 127.6, 46.6, 42.8, 42.8, 42.7, 39.8, 32.5, 31.4, 31.3, 25.9, 25.4, 23.5, 23.4, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C25H3579BrO3Na 485.1662, found 485.1662; [M+Na]+ calcd for C25H3581BrO3Na 487.1642, found 487.1642. 1,1'-(6-iodo-3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4af): Yellow soild, mp 57.2 – 57.7 oC; yield, 48.7 mg, 48%; Rf = 0.14 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.66 (s, 1H), 7.51 (s, 1H), 3.24 (dd, J = 17.3, 8.0 Hz, 1H), 3.19 – 3.10 (m, 2H), 2.70 – 2.65 (m, 3H), 2.60 – 2.55 (m, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.36 (t, J = 7.5 Hz, 2H), 2.06 – 2.00 (m, 1H), 1.85 – 1.79 (m, 1H), 1.58 – 1.51 (m, 4H), 1.29 – 1.21 (m, 8H), 0.86 (q, J = 7.1 Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.4, 209.8, 207.9, 155.8, 143.5, 137.9, 133.8, 133.0, 103.0, 46.4, 42.8, 42.8, 42.6, 39.8, 32.3, 31.3, 31.3, 25.8, 25.4, 23.5, 23.4, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C25H35IO3Na 533.1523, found 533.1522. 1,1'-(5-methoxy-3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4ag): White soild, mp 36.1 – 37.5 oC; yield, 29.9 mg, 36%; Rf = 0.44 (hexanes/EtOAc = 5/1); 1H NMR (600 MHz, CDCl3) δ 7.12 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H), 3.25 – 3.12 (m, 3H), 2.69 (t, J = 7.4 Hz, 2H), 2.64 – 2.56 (m, 4H), 2.42 (t, J = 7.5 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 2.11 – 2.05 (m, 1H), 1.86 – 1.80 (m, 1H), 1.59 – 1.53 (m, 4H), 1.32 – 1.23 (m, 8H), 0.90 – 0.85 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.8, 210.6, 209.0, 155.2, 143.1, 134.6, 133.0, 130.0, 114.7, 55.4, 46.3, 43.6, 42.8, 42.7, 39.9, 31.4, 31.4, 29.2, 25.7, 25.6, 23.5, 23.4, 22.4, 13.9; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C26H38O4Na 437.2662, found 437.2654.

1,1'-(5,7-dimethoxy-3-oxo-2,3-dihydro-1H-indene-2,4-diyl)bis(octan-3-one) (4ah): Orange soild, mp 43.8 – 45.2 oC; yield, 47.9 mg, 54%; Rf = 0.27 (hexanes/EtOAc = 5/1); 1H NMR (600 MHz, CDCl3) δ 6.62 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.27 – 3.20 (m, 2H), 3.13 (dd, J = 16.9, 7.8 Hz, 1H), 2.59 (t, J = 7.5 Hz, 3H), 2.56 – 2.50 (m, 3H), 2.46 – 2.40 (m, 4H), 2.08 – 2.02 (m, 1H), 1.85 – 1.79 (m, 1H), 1.59 – 1.54 (m, 4H), 1.30 – 1.24 (m, 8H), 0.88 (t, J = 7.0 Hz, 6H);

13C{1H}

NMR (150 MHz, CDCl3) δ 211.3, 210.7, 209.1, 157.8, 155.2,

135.1, 134.2, 120.4, 100.2, 56.4, 55.5, 46.7, 42.7, 42.3, 39.9, 31.4, 31.3, 28.2, 25.5, 23.5, 23.4, 22.4, 22.4, 18.4, 13.9, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C27H40O5Na 467.2768, found 467.2757.

4,6-dimethyl-2-(3-oxooctyl)-2,3-dihydro-1H-inden-1-one (4ai): Yellow oil; yield, 16.5 mg, 29%; Rf = 0.33 (hexanes/EtOAc = 10/1); 1H NMR (600 MHz, CDCl3) δ 7.29 (s, 1H), 7.16 (s, 1H), 3.11 (dd, J = 16.9, 7.7 Hz, 1H), 2.60 – 2.49 (m, 4H), 2.35 (t, J = 7.4 Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.02 – 1.96 (m, 1H), 1.84 – 1.78 (m, 1H), 1.53 – 1.47 (m, 2H), 1.24 – 1.17 (m, 4H), 0.81 (t, J = 7.1 Hz, 3H);

13C{1H}

NMR (150 MHz,

CDCl3) δ 210.7, 208.7, 149.8, 137.5, 136.5, 135.2, 121.1, 46.3, 42.8, 39.9, 31.4, 31.3, 25.5, 23.4, 22.4, 20.9, 17.6, 13.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H26O2Na 309.1825, found 309.1818. 28


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4-fluoro-7-methyl-2-(3-oxopentyl)-2,3-dihydro-1H-inden-1-one (4aj): Yellow oil; yield, 29.0 mg, 58%; Rf = 0.24 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.10 (t, J = 8.2 Hz, 1H), 7.07 – 7.05 (m, 1H), 3.29 (dd, J = 17.3, 8.0 Hz, 1H), 2.69 (dd, J = 17.3, 4.1 Hz, 1H), 2.66 – 2.61 (m, 3H), 2.56 (s, 3H), 2.46 (q, J = 7.3 Hz, 2H), 2.10 – 2.04 (m, 1H), 1.90 – 1.84 (m, 1H), 1.06 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.7, 208.0, 158.1 (d, JC-F = 245.1 Hz), 139.4 (d, JC-F = 19.4 Hz), 135.9 (d, JC-F = 4.2 Hz), 134.4 (d, JC-F = 4.0 Hz), 130.8 (d, JC-F = 5.7 Hz), 120.0 (d, JC-F = 19.8 Hz), 46.2, 39.4, 35.9, 28.1, 25.5, 17.5, 7.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H17FO2Na 271.1105, found 271.1101. 4-fluoro-7-methyl-2-(3-oxononyl)-2,3-dihydro-1H-inden-1-one (4ak): Yellow oil; yield, 46.7 mg, 77%; Rf = 0.30 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.11 (t, J = 8.2 Hz, 1H), 7.08 – 7.05 (m, 1H), 3.30 (dd, J = 17.3, 8.0 Hz, 1H), 2.69 (dd, J = 17.3, 4.1 Hz, 1H), 2.66 – 2.62 (m, 3H), 2.56 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.10 – 2.04 (m, 1H), 1.89 – 1.83 (m, 1H), 1.60 – 1.53 (m, 2H), 1.30 – 1.26 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H);

13C{1H}


139.4 (d, JC-F = 19.4 Hz), 135.9 (d, JC-F = 4.2 Hz), 134.4 (d, JC-F = 3.9 Hz), 130.8 (d, JC-F = 5.7 Hz), 120.0 (d, JC-F = 19.8 Hz), 46.2, 42.9, 39.8, 31.6, 28.9, 28.1, 25.5, 23.8, 22.5, 17.5, 14.0; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H25FO2Na 327.1731, found 327.1727. 4-fluoro-7-methyl-2-(3-oxodecyl)-2,3-dihydro-1H-inden-1-one (4al): Yellow oil; yield, 49.4 mg, 78%; Rf = 0.30 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.10 (t, J = 8.2 Hz, 1H), 7.07 – 7.05 (m, 1H), 3.29 (dd, J = 17.3, 8.0 Hz, 1H), 2.68 (dd, J = 17.3, 4.1 Hz, 1H), 2.65 – 2.61 (m, 3H), 2.55 (s, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.09 – 2.03 (m, 1H), 1.89 – 1.81 (m, 1H), 1.59 – 1.53 (m, 2H), 1.29 – 1.26 (m, 8H), 0.86 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.4, 208.0, 158.1 (d, JC-F = 245.1 Hz), 139.4 (d, JC-F = 19.4 Hz), 135.9 (d, JC-F = 4.3 Hz), 134.4 (d, JC-F = 3.9 Hz), 130.8 (d, JC-F = 5.7 Hz), 120.0 (d, JC-F = 19.8 Hz), 46.2, 42.9, 39.7, 31.6, 29.2, 29.0, 28.1, 25.4, 23.8, 22.5, 17.5, 14.0; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H27FO2Na 341.1887, found 341.1884. 4-fluoro-7-methyl-2-(3-oxoundecyl)-2,3-dihydro-1H-inden-1-one (4am): Yellow oil; yield, 49.2 mg, 74%; Rf = 0.30 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.11 (t, J = 8.2 Hz, 1H), 7.09 – 7.05 (m, 1H), 3.30 (dd, J = 17.3, 8.0 Hz, 1H), 2.70 (dd, J = 17.3, 4.0 Hz, 1H), 2.67 – 2.59 (m, 3H), 2.57 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.10 – 2.04 (m, 1H), 1.90 – 1.84 (m, 1H), 1.60 – 1.54 (m, 2H), 1.27 (s, 10H), 0.87 (t, J = 7.1 Hz, 3H);

13C{1H}


139.4 (d, JC-F = 19.4 Hz), 135.9 (d, JC-F = 4.2 Hz), 134.4 (d, JC-F = 3.9 Hz), 130.8 (d, JC-F = 5.7 Hz), 120.0 29



(d, JC-F = 19.8 Hz), 46.2, 42.9, 39.8, 31.8, 29.3, 29.2, 29.1, 28.1, 25.5, 23.8, 22.6, 17.5, 14.1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H29FO2Na 355.2044, found 355.2035. 4-fluoro-7-methyl-2-(3-oxododecyl)-2,3-dihydro-1H-inden-1-one (4an): Yellow solid, mp 31.8 – 32.4 oC;

yield, 53.0 mg, 77%; Rf = 0.24 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.10 (t, J = 8.2

Hz, 1H), 7.07 – 7.05 (m, 1H), 3.29 (dd, J = 17.3, 8.0 Hz, 1H), 2.69 (dd, J = 17.3, 4.1 Hz, 1H), 2.66 – 2.61 (m, 3H), 2.56 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.09 – 2.03 (m, 1H), 1.89 – 1.83 (m, 1H), 1.60 – 1.53 (m, 2H), 1.25 (d, J = 9.4 Hz, 12H), 0.86 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.5, 208.0, 158.1 (d, JC-F = 245.2 Hz), 139.4 (d, JC-F = 19.4 Hz), 135.9 (d, JC-F = 4.2 Hz), 134.4 (d, JC-F = 3.9 Hz), 130.8 (d, JC-F = 5.7 Hz), 120.0 (d, JC-F = 19.8 Hz), 46.2, 42.9, 39.8, 31.8, 29.4, 29.4, 29.2, 28.1, 25.5, 23.8, 22.6, 17.5, 14.0; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C22H31FO2Na 369.2200, found 369.2194. 4-fluoro-7-methyl-2-(3-oxotetradecyl)-2,3-dihydro-1H-inden-1-one (4ao): Yellow solid, mp 44.0 – 44.9 oC;

yield, 54.2 mg, 72%; Rf = 0.26 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 7.11 (t, J = 8.2

Hz, 1H), 7.08 – 7.06 (m, 1H), 3.30 (dd, J = 17.3, 8.0 Hz, 1H), 2.69 (dd, J = 17.3, 4.1 Hz, 1H), 2.66 – 2.59 (m, 3H), 2.56 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.10 – 2.03 (m, 1H), 1.89 – 1.83 (m, 1H), 1.60 – 1.53 (m, 2H), 1.28 – 1.22 (m, 16H), 0.87 (t, J = 7.0 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 210.5, 208.0,

158.1 (d, JC-F = 245.3 Hz), 139.4 (d, JC-F = 19.4 Hz), 136.0 (d, JC-F = 4.3 Hz), 134.4 (d, JC-F = 3.8 Hz), 130.8 (d, JC-F = 5.7 Hz), 120.0 (d, JC-F = 19.8 Hz), 46.2, 42.9, 39.8, 31.9, 29.6, 29.4, 29.4, 29.3, 29.2, 28.1, 25.5, 23.8, 22.6, 17.5, 14.1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H35FO2Na 397.2513, found 397.2511. 4-fluoro-7-methyl-2-(3-oxo-5-phenylpentyl)-2,3-dihydro-1H-inden-1-one (4ap): Yellow oil; yield, 53.1 mg, 82%; Rf = 0.22 (hexanes/EtOAc = 20/1); 1H NMR (600 MHz, CDCl3) δ 7.29 – 7.25 (m, 2H), 7.20 – 7.17 (m, 3H), 7.11 (t, J = 8.2 Hz, 1H), 7.08 – 7.06 (m, 1H), 3.27 (dd, J = 17.2, 7.9 Hz, 1H), 2.91 (t, J = 7.6 Hz, 2H), 2.79 – 2.76 (m, 2H), 2.68 – 2.59 (m, 4H), 2.57 (s, 3H), 2.10 – 2.04 (m, 1H), 1.89 – 1.83 (m, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 209.2, 208.0 (d, JC-F = 2.5 Hz), 158.1 (d, JC-F = 245.1 Hz), 140.9,

139.4 (d, JC-F = 19.4 Hz), 135.9 (d, JC-F = 4.3 Hz), 134.4 (d, JC-F = 4.0 Hz), 130.8 (d, JC-F = 5.8 Hz), 128.5, 128.3, 126.1, 120.0 (d, JC-F = 19.8 Hz), 46.1, 44.3, 40.0, 29.7, 28.1, 25.3, 17.5; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H21FO2Na 347.1418, found 347.1414. 4-fluoro-7-methyl-2-(3-oxo-3-phenylpropyl)-2,3-dihydro-1H-inden-1-one(4aq): Yellow soild, mp 81.1 – 81.5 oC; yield, 44.7 mg, 76%; Rf = 0.17 (hexanes/EtOAc = 25/1); 1H NMR (600 MHz, CDCl3) δ 8.01 – 7.95 (m, 2H), 7.58 – 7.53 (m, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.11 (t, J = 8.2 Hz, 1H), 7.08 – 7.06 (m, 1H), 30


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3.39 – 3.33 (m, 1H), 3.26 – 3.20 (m, 2H), 2.80 – 2.73 (m, 2H), 2.58 (s, 3H), 2.28 – 2.21 (m, 1H), 2.09 – 2.03 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 208.0, 199.5, 158.1 (d, JC-F = 245.1 Hz), 139.4 (d, JC-F = 19.4 Hz), 136.8, 136.0 (d, JC-F = 4.2 Hz), 134.4 (d, JC-F = 3.9 Hz), 133.0, 130.8 (d, JC-F = 5.7 Hz), 128.6, 128.0, 120.0 (d, JC-F = 19.8 Hz), 46.4, 35.8, 28.2, 26.0, 17.5; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C19H17FO2Na 319.1105; found 319.1106. Experimental procedure for the synthesis of 6a An oven-dried microwave vial was charged with [RuCl2(p-cymene)]2 (Ru*, 3.1 mg, 5 mol%, 0.005 mmol), Mn(OAc)2 (13.0 mg, 0.075 mmol), o-toluic acid (0.1 mmol, 13.6 mg), ethyl vinyl ketone (0.25 mmol, 24.7 μL). After the tube was evacuated and purged with argon three times, DCE (0.6 mL) were added to the system by syringe. The mixture was stirred at 150 °C (oil bath temperature) for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc (5 mL) and filtered through a short silica gel pad. The filter cake was further flushed with EtOAc (10 mL). The combined solution was concentrated under vacuum, and the residue was purified by a preparative TLC to afford the corresponding product. Yellow oil; yield, 4.6 mg, 16%; Rf = 0.16 (hexanes/EtOAc = 15/1); 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 3.67 (d, J = 17.5 Hz, 1H), 2.82 (d, J = 17.5 Hz, 1H), 2.65 – 2.51 (m, 5H), 2.41 – 2.33 (m, 4H), 2.32 – 2.20 (m, 2H), 1.04 – 0.98 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 209.9, 207.0, 204.2, 153.5, 139.6, 134.7, 132.8, 129.6, 123.7, 67.0, 37.3, 35.8, 34.8, 31.5, 28.6, 18.2, 7.8, 7.6; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C18H22O3Na 309.1461, found 309.1469. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Mechanistic studies, X-ray crystal structure and data of 3q and 4a, 1H and compounds (PDF) X-ray data (CIF) AUTHOR INFORMATION Corresponding Author E-mail: [email protected]. ORCID 31


13C

NMR spectra for all


Xian-Ying Shi: 0000-0003-3883-2518 Notes The authors declare no competing financial interest. ACKNOWLEGEMENTS The authors are grateful to the National Natural Science Foundation of China (Grant No. 21776171, 21636006 and 21572122), the Fundamental Research Funds for the Central Universities (Grant No. GK 201703019 and GK 201601005) for providing financial supports.

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Divergent Syntheses of Spiroindanones and 2-Substituted 1

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