Visible-Light-Induced Intermolecular Dearomative Cyclization of

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Visible-Light-Induced Intermolecular Dearomative Cyclization of Furans: Synthesis of 1-Oxaspiro[4.4]nona-3,6-dien-2-one Wuheng Dong, Yao Yuan, Xiaoshuang Gao, Miladili Keranmu, Wanfang Li, Xiaomin Xie, and Zhaoguo Zhang J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 03 Jan 2019 Downloaded from http://pubs.acs.org on January 3, 2019

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The Journal of Organic Chemistry

Visible-Light-Induced Intermolecular Dearomative Cyclization of Furans: Synthesis of 1-Oxaspiro[4.4]nona-3,6-dien-2-one Wuheng Dong, † Yao Yuan, † Xiaoshuang Gao, †Miladili Keranmu, † Wanfang Li, † Xiaomin Xie, † and Zhaoguo Zhang*, †,‡ †

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China

‡

Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China Fax: (+86)-21-5474-8925; phone: (+86)-21-5474-8925; E-mail: [email protected]

ABSTRACT A

fac-Ir(ppy)3-catalyzed

intermolecular

dearomative

cyclization

of

2-bromo-2-((5-bromofuran-2-yl)methyl)malonate and alkynes affording substituted spirolactones in yields of 19 to 91% via a 5-exo-dig radical cyclization under visible light is presented. This method provides a new access to the synthesis of spirocycle skeletons applying water as an external oxygen source under mild reaction conditions.

INTRODUCTION Radical cascade cyclization reactions represent a useful strategy for the rapid construction of novel and complex cyclic molecular structures from readily accessible starting materials in a concise manner.1 While in a traditional radical reaction, poisonous radical initiator or harsh conditions was usually used for radical generation, and a tremendous effort has been made to seek more environmentally friendly alternatives for producing radical. In the past decade, the visible-light-induced photoredox catalysis reaction provides a highly attractive and useful synthetic tool to generate many reactive radicals for the construction of functionalized compounds and thus has received much attention due to its green, safe and sustainable features.2 The spirocyclic skeletons are frequently found in many biologically active molecules and natural products. Among them, spirolactone units are an important family of these significant structures, which occur in many natural products, such as (-)-securinine,3 (S)-(-)-longianone,4 secosyrin5 and hyperolactone.6

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Not surprisingly, the development of simple and efficient methods for high regioselective access to this spiro-scaffold is of great interest to synthetic organic chemists. Among several synthetic routes, the radical dearomative cyclization of furans is a rapid approach for the construction of spirolactone from readily available material. Recently, the spirolactone skeleton has been synthesized, involving the oxidative dearomatization reaction by intramolecular radical cyclisation onto a furan in the presence of stoichiometric amounts of dilauroyl peroxide (DLP) and further oxidize the acetal to lactone by using mCPBA (Scheme 1a).7 In 2013, Reiser and co-workers reported an elegant method for the direct synthesis of this spiro-scaffold via visible-light photocatalytic decarboxylative alkyl radical spirocyclization onto furans starting from alkyl N-(acyloxy)-phthalimide (NHP ester). The reaction was performed in acetonitrile with water as an external oxygen source at room temperature in moderate yields (19%-61%, Scheme 1b).8 Scheme 1. Radical spirocyclization onto furan

Recently, we reported an efficient coupling of alkynes and 2-bromo-1,3-dicarbonyl compounds for the synthesis of functionalized spirocarbocycle via visible light-induced intermolecular dearomative reaction (Scheme 1c).9 Inspired by these work,8-9 we speculated that furan could replace benzene to give the corresponding spirolactone (Scheme 1d). Herein, we disclose the preparation of substituted spirolactones from readily available starting materials by photoredox catalyst.


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RESULTS AND DISCUSSION We

initiated

our

study

by

examining

the

reaction

of

ethynylbenzene

(1a)

and

diethyl

2-bromo-2-((5-bromofuran-2-yl)methyl)malonate (2a) with fac-Ir(ppy)3 (1 mol %) in DMA under a 7 W blue LED irradiation. When 50 equiv. of H2O (DMA/H2O=10:1) were added to this system, the desired product, spirolactone 3aa, was obtained, albeit in low yields (24% yield, Table 1, entry 1). Encouraged by the preliminary result, we then embarked on optimizing the reaction conditions to improve the yield of 3aa. First, an extensive screening of solvent was conducted and we found that a marked increase in yield was obtained when employing acetonitrile as the solvent, affording 3aa in 62% yield (Table 1, entries 2-6). In our previously reported dearomative reaction,9 we took advantage of external base to neutralize the hydrobromic acid generated thereof and got an increased yield of the target product. However, the addition of extra bases to the reaction, including organic and inorganic bases, led to the decreased yield of 3aa (Table 1, entries 7-11). Even lower yield (10%) was obtained when Na2SO3 was used as reductive base.10 Considering that water could play an important role in this transformation, such as reacting with carbocation and the cleavage of the C-Br bond, we turned our attention to screen the amount of water. When the water loading was increased to 62 equiv (CH3CN/H2O=8:1), we were pleased to find that the yield of 3aa could be increased to 69%. (Table 1, entry 13). Moreover, addition of more or less water led to slight decreased yields, especially, almost no product was observed when the amount of water was decreased to 5 equiv (CH3CN/H2O=100:1) (Table 1, entries 14-19). Subsequently, the ratio of 1a and 2a was examined. The results demonstrated that the optimal ratio was 1:1.5, and the yield of the target product 3aa could significantly increase to 75% (Table 1, entries 20-21). To our delight, the yield could be further increased to 80% when the ratio was changed to 1:2 (Table 1, entry 22). A slightly diluted reaction mixture resulted in a significant increase of the yield and a 90% isolated yield was obtained (Table 1, entry 23). However, further diluted or concentrated reaction conditions led to a decreased in reaction efficiency (Table 1, entries 24-25). Finally, control experiments of this radical dearomative reaction were performed, and no product was obtained when the reaction was conducted either in the absence of a photocatalyst or in the dark, confirming that this transformation was a photocatalytic process (Table 1, entries 26-28). Table 1, Optimization of the reaction conditions a)



entry

1a:2a

solvent

yieldb (%)

1

2:1

DMA/H2O=10:1

24

2

2:1

DMF/H2O=10:1

28

3

2:1

MeOH/H2O=10:1

31

4

2:1

DMSO/H2O=10:1

25

5

2:1

THF/H2O=10:1

38

6

2:1

CH3CN/H2O=10:1

62

7

c

2:1

CH3CN/H2O=10:1

25

8

d

2:1

CH3CN/H2O=10:1

14

9

e

2:1

CH3CN/H2O=10:1

22

10 f

2:1

CH3CN/H2O=10:1

28

g

2:1

CH3CN/H2O=10:1

10

12

2:1

CH3CN/H2O=9:1

68

13

2:1

CH3CN/H2O=8:1

69

14

2:1

CH3CN/H2O=7:1

64

15

2:1

CH3CN/H2O=6:1

63

16

2:1

CH3CN/H2O=5:1

60

17

2:1

CH3CN/H2O=30:1

44

18

2:1

CH3CN/H2O=50:1

21

19

2:1

CH3CN/H2O=100:1

trace

20

1:1

CH3CN/H2O=8:1

62

21

1:1.5

CH3CN/H2O=8:1

75

22

11

1:2

CH3CN/H2O=8:1

80

h

1:2

CH3CN/H2O=8:1

90 (90) i

24 j

1:2

CH3CN/H2O=8:1

78

25

k

1:2

CH3CN/H2O=8:1

66

26

l

1:2

CH3CN/H2O=8:1

0

27

m

1:2

CH3CN

0

28

n

1:2

CH3CN/H2O=8:1

0

23

a)

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Unless otherwise noted, reactions were performed on a 0.3 mmol scale of 1a or 2a, fac-Ir(ppy)3 (4.2

mg, 1 mol %), solvent (3 mL), irradiation with a 7 W blue LED at rt for 12 h. reported using benzyl ether as an internal standard.

c)

Pyridine (2.2 equiv.).

d)

b) 1

H NMR yields were

2,6-Lutidine (2.2 equiv.). e)

Na2CO3 (2.2 equiv.). f) NaHCO3 (2.2 equiv.). g) NaHSO3 (2.2 equiv.). h) Solvent (5 mL). i) Isolated yield. j) Solvent (10 mL). k) Solvent (1.5 mL). l) Without photocatalyst. m) Without water. n) Reaction was carried out in the dark.

With the reaction conditions established, we next investigated the scope of substrates for this protocol, and the results are listed in Scheme 2. Ethynylbenzene with an electron-donating group on the para-position of the benzene ring afforded the desired spirolactones in moderate to good yields (Scheme 2, 3aa-3ca). Interestingly, the transformation was also compatible with halogen groups, such as fluoride, chloride, and bromide, which provided new opportunities for the functionalized products


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via

cross-couplings

(3da-3fa).

When

the

phenyl

ring

was

functionalized

with

strong

electron-withdrawing group such as cyano, alkoxycarbonyl, and trifluoromethyl, moderate to good yields of the desired products were obtained. It seemed that a minor steric hindrance did not impose any negative effect on reaction efficiency, and a good yield of target product was obtained (3ja). Moreover, substrates with a methyl or fluoro group at the metal-position also afforded the corresponding spirolactones in excellent yields (3ja-3la). When linear and functionalized aliphatic alkynes were used as the reaction partners, the corresponding products (3ma-3oa) were obtained in moderate yields. In addition, acetylene with a large sterically hindered group (TMS) was also amenable to this dearomative cyclization albeit in lower yield even with increased amounts of alkyne starting material (5 equiv.). The scope of the reaction was next examined with respect to the internal alkynes. 1-Phenylpropyne (1p) showed much lower reactivity in this reaction, and the desired product 3pa was obtained in only 19% yield. However, no product was obtained when diphenyl acetylene or methyl phenylpropiolate was employed under the same conditions, and the starting materials were fully recovered. Given the prevalence of heterocycles in medicinal chemistry, we also investigated the scope of heterocyclic substrates. Heteroaryl acetylenes containing the 2-thiophene and 3-thiophene could all also participate in this transformation to give the desired product in 62% and 72% yield, respectively. Under the optimized conditions, 2d proved to be a substrate to provide the target products in 67% yield as a mixture of syn- and anti-isomer. Howerver, secondary bromide 2e failed to give the desired product 3ae and the starting materials were fully recovered, which indicated that two electron-withdrawing groups were necessary for the -bromocarbonyl compounds. If 2a was replaced by diethyl 2-bromo-2-((5-bromothiophen-2-yl)methyl)malonate (2f), the corresponding diethyl 2-oxo-9-phenyl-1-thiaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3af) was obtained in 40% yield. Scheme 2. Substrate scope of varies alkynesa



a

Conditions: 1 (0.3 mmol), 2 (0.6 mmol), fac-Ir(ppy)3 (4.2 mg, 1 mol %),

CH3CN:H2O = 8:1 (5 mL), irradiation with 7 W blue LED at rt for 12 h; isolated yields were given. b 1:2a = 5:1.

In addition, we also investigated the reactivity of other leaving groups on the furan moiety under the optimal conditions (Scheme 3). When the furan ring was functionalized with a chloric group, the

substrate 2b was also compatible with the dearomatization reaction and good yield of the desired product 3aa was obtained. However, under the same conditions for 2c, this transformation still proceeded, albeit in low yields (20%), suggesting that the dearomative cyclization involving C-H cleavage would be less reactive than C-X (X=Br, Cl). Scheme 3. Substrate scope of varies alkynesa

a

Conditions: 1a (30.64 mg, 0.3 mmol), 2 (0.6 mmol), fac-Ir(ppy)3 (4.2 mg, 1 mol %),

CH3CN:H2O = 8:1 (5 mL), irradiation with 7 W blue LED at rt for 12 h; isolated yields


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were given.

Finally, a

18

O-labelled verification experiment was designed and performed as shown in Scheme 4.

When the H2O was replaced by H218O, the desired product 3aa containing the 18O-atom was obtained in 85% yield, which implied the oxygen atom of the newly-formed carbonyl group should come from H2O in the C-Br bond cleavage process. Scheme 4. 18O-labelled verification experiment a

a

Conditions: 1a (10.2 mg, 0.1 mmol), 2a (79.6 mg, 0.2 mmol), fac-Ir(ppy)3 (1.1 mg, 1

mol %), CH3CN:H218O = 8:1 (1.7 mL), irradiation with 7 W blue LED at rt for 12 h; isolated yields were given.

On the basis of the control experiments and related reports,7-9,11 we propose a plausible mechanism to account for this transformation as shown in Scheme 5. First, the photocatalyst was excited to excited IrIII* species under visible light irradiation, then it underwent a single electron transfer process with 2a to give IrIV and electron radical A. Subsequently, A with ethynylbenzene (1a) underwent a rapid addition to afford the radical intermediate B. A 5-exo-trig radical cyclization then took place on the furan, generating the key radical C, which would be oxidized by IrIV metal complex to form the cation intermediate D and finally finished the photoredox catalytic cycle. The desired product 3aa would be generated from intermediate D in the presence of water. Scheme 5. Proposed mechanism for the catalysis

CONCLUSION In

summary,

an

efficient

photocatalyzed

intermolecular


dearomative

cyclization

of


2-bromo-2-((5-bromofuran-2-yl)methyl)malonate and alkynes for the synthesis of substituted spirolactones in moderate to good yields was developed. This photocatalytic approach provided a novel access to construct complex spirocarbocycle structures with a broad substrate scope under mild conditions. The application of photoredox catalysis to construct the biologically important molecules is ongoing in our laboratory.

EXPERIMENTAL SECTION General Procedures. Unless otherwise noted, all reactions were carried out under an atmosphere of nitrogen using standard Schlenk techniques. Materials were purchased from commercial suppliers and used without further purification. 1H NMR and 13C NMR spectra were recorded on a 400 or 500 MHz spectrometer. The chemical shifts for 1H NMR were recorded in ppm downfield from tetramethylsilane (TMS) with the solvent resonance as the internal standard. The chemical shifts for 13C NMR were recorded in ppm downfield using the central peak of deuterochloroform (77.16 ppm) as the internal standard. Coupling constants (J) are reported in Hz and refer to apparent peak multiplications. HRMS were obtained on an ESI-TOF mass spectrometer. Flash column chromatography was performed on silica gel (300-400 mesh). Typical Procedure for the Preparation of 2a-2c.9,12 To a solution of 5-bromofuran-2-carbaldehyde (8.75 g, 50 mmol) in EtOH (100 mL) taken in a 250 mL round-bottom flask at 0 oC was added NaBH4 (1.89 g, 50 mmol). The mixture was warmed to room temperature for 12 h. After completion monitored by TLC, the mixture was quenched with water (20 mL) and the EtOH was removed under reduced pressure. Then, the mixture was extracted with DCM (3 × 80 mL), dried over Na2SO4 and concentrated. The crude product (5-bromofuran-2-yl)methanol (not stable upon storage) was immediately used for next step without additional purification. A 250 mL round-bottom flask was charged with (5-bromofuran-2-yl)methanol (8.85 g, 50 mmol) in anhydrous diethyl ether (150 mL) was added PBr3 (13.53 g, 50 mmol) at 0 oC under N2 atmosphere over 40 min. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a flask containing 80 g ice. The layers were separated and the organic phase was washed with water (1 × 80 mL) and brine (1 × 80 mL). The solvent was removed under reduced pressure, and the crude product 2-bromo-5-(bromomethyl)furan (not stable upon storage) was rapidly taken to the next step without purification. To a solution of diethyl 2-bromomalonate (5.98 g, 25.0 mmol) in anhydrous DMF (40 mL) was added potassium carbonate (4.49 g, 36.81 mmol) and 2-bromo-5-(bromomethyl)furan (9.00 g, 37.5 mmol). The mixture was stirred at room temperature for 12 h. Then, the mixture was transfered into a separatory funnel


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containing Et2O and H2O. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica-gel

column

chromatography

eluting

with

PE

/

EA

(30:1)

to

give

2-bromo-2-(4-methoxybenzyl)malonate as colorless liquid (6.23 g, 63% yield). Diethyl 2-bromo-2-((5-bromofuran-2-yl)methyl)malonate (2a). Colorless liquid, 6.23 g, 63% yield. 1H NMR (400 MHz, CDCl3) δ 6.23 (q, J = 3.2 Hz, 2H), 4.30 (q, J = 7.2 Hz, 4H), 3.67 (s, 2H), 1.31 (t, J = 6.8 Hz, 6H).

13

C {1H} NMR (100 MHz, CDCl3) δ 166.3, 151.1, 121.3, 112.7, 112.3, 63.6, 60.6, 37.6, 14.1.

HRMS (ESI, TOF) (m/z): Calculated for C12H15Br2O5 (M + H)+: 396.9286, Found: 396.9293. Diethyl 2-bromo-2-((5-chlorofuran-2-yl)methyl)malonate (2b). Colorless liquid, 3.81 g, 72% yield. 1H NMR (500 MHz, CDCl3) δ 6.24 (d, J = 3.5 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 4.30 (q, J = 7.5 Hz, 4H), 3.64 (s, 2H), 1.31 (t, J = 7.0 Hz, 6H). 13C {1H} NMR (125 MHz, CDCl3) δ 166.0, 148.5, 135.4, 112.0, 106.9, 63.2, 60.3, 37.2, 13.7. HRMS-ESI (m/z): Calculated for C12H15BrClO5 (M + H)+: 352.9791, Found: 352.9791. Diethyl 2-bromo-2-(furan-2-ylmethyl)malonate (2c). Colorless liquid, 3.16 g, 49% yield. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 3.6, 2.0 Hz, 1H), 6.23 (d, J = 3.6 Hz, 1H), 4.30 (q, J = 7.2 Hz, 4H), 3.70 (s, 2H), 1.29 (t, J = 7.2 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.4, 149.0, 142.3, 110.5, 109.6, 63.3, 61.0, 37.3, 13.9. HRMS (ESI, TOF) (m/z): Calculated for C12H16BrO5 (M + H)+: 319.0181, Found: 319.0181. Ethyl 2-bromo-2-((5-bromofuran-2-yl)methyl)-3-oxobutanoate (2d). The procedure was adopted from the literature. 9 Yellow liquid, 0.59 g, 32% yield. 1H NMR (400 MHz, CDCl3) δ 6.21 - 6.18 (m 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.64 (d, J = 16.0 Hz, 1H), 3.51 (d, J = 16.0 Hz, 1H), 2.39 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13

C {1H} NMR (100 MHz, CDCl3) δ 196.8, 166.8, 151.3, 121.0, 112.5, 112.3, 66.1, 63.7, 36.3, 26.3, 14.0.

HRMS (ESI, TOF) (m/z): Calculated for C11H12Br2O4Na (M + Na)+: 388.9000, Found: 388.8997. Ethyl 2-bromo-3-(5-bromofuran-2-yl)propanoate (2e). The procedure was adopted from the literature. 9 Yellow liquid, 0.64 g, 39% yield. 1H NMR (400 MHz, CDCl3) δ 6.20 (d, J = 3.2 Hz, 1H), 6.13 (d, J = 3.2 Hz, 1H), 4.42 (t, J = 7.2 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.45 (dd, J = 15.2, 7.6 Hz, 1H), 3.23 (dd, J = 15.2, 6.8 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 169.0, 152.7, 121.0, 112.2, 111.0, 62.3, 42.1, 34.0, 14.0. HRMS (ESI, TOF) (m/z): Calculated for C9H10Br2O3Na (M + Na)+: 346.8894, Found: 346.8853. Diethyl 2-bromo-2-((5-bromothiophen-2-yl)methyl)malonate (2f). Yellow liquid, 2.07 g, 50% yield. 1H NMR (400 MHz, CDCl3) δ 6.87 (d, J = 3.6 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.76



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(s, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.2, 137.4, 129.4, 129.2, 112.0, 63.5, 62.1, 39.2, 13.9. HRMS (ESI, TOF) (m/z): Calculated for C12H15Br2O4S (M + H)+: 412.9058, Found: 412.9056. Typical

Procedure

for

fac-Ir(ppy)3-catalyzed

intermolecular

dearomative

cyclization

of

2-bromo-2-((5-bromofuran-2-yl)methyl)malonate and alkynes. To a 25 mL dried Schlenk flask equipped with a magnetic stir bar was added 1a (30.6 mg, 0.30 mmol), 2a (238.8 mg, 0.60 mmol), fac-Ir(ppy)3 (4.2 mg, 0.003 mmol). Then 5 mL mixed solvent (CH3CN:H2O=8:1) was added into the reaction tube via a syringe. The resulting mixture was degassed by the freeze-pump-thaw method and then stirred at a distance of ~5 cm from a 7 W blue LED bulb at room temperature for 12 h. After the completion of the reaction, the mixture was concentrated and the pure product was obtained by flash chromatography on silica-gel (PE / EA = 5:1). Diethyl 2-oxo-9-phenyl-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3aa). Yellow liquid, 96.8 mg, 90% yield. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 5.6 Hz, 1H), 7.32 – 7.26 (m, 5H), 6.37 (s, 1H), 6.07 (d, J = 5.6 Hz, 1H), 4.34 – 4.20 (m, 4H), 3.06 (d, J = 14.4 Hz, 1H), 2.92 (d, J = 14.4 Hz, 1H), 1.30 (td, J = 7.2, 2.0 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.1, 170.0, 169.3, 158.3, 144.9, 132.6, 131.7, 129.1, 128.7, 127.4, 121.3, 97.6, 63.3, 62.6, 62.2, 41.9, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C20H21O6 (M + H)+: 357.1338, Found: 357.1334. Diethyl 2-oxo-9-(p-tolyl)-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3ba). Yellow liquid, 84.3 mg, 76% yield. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.33 (s, 1H), 6.06 (d, J = 5.6 Hz, 1H), 4.31 – 4.21 (m, 4H), 3.05 (d, J = 14.4 Hz, 1H), 2.90 (d, J = 14.4 Hz, 1H), 2.31 (s, 3H), 1.30 (td, J = 7.2, 2.4 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.1, 170.0, 169.3, 158.4, 144.7, 139.0, 130.9, 129.6, 129.3, 127.2, 121.1, 97.6, 63.2, 62.5, 62.1, 41.8, 21.2, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C21H23O6 (M + H)+: 371.1495, Found: 371.1492. Diethyl 9-(4-methoxyphenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3ca). Yellow liquid, 67.8 mg, 58% yield. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 5.6 Hz, 1H), 7.24 – 7.19 (m, 2H), 6.83 – 6.79 (m, 2H), 6.29 (s, 1H), 6.07 (d, J = 5.6 Hz, 1H), 4.31 – 4.21 (m, 4H), 3.78 (s, 3H), 3.04 (d, J = 14.4 Hz, 1H), 2.89 (d, J = 14.4 Hz, 1H), 1.30 (td, J = 7.2, 2.0 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.2, 170.1, 169.4, 160.2, 158.6, 144.2, 130.1, 128.6, 124.9, 121.1, 114.0, 97.7, 63.1, 62.5, 62.1, 55.3, 41.8, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C21H23O7 (M + H)+: 387.1444, Found: 387.1443. Diethyl 9-(4-fluorophenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3da). Yellow liquid,


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102.1 mg, 91% yield. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 5.6 Hz, 1H), 7.26 – 7.23 (m, 2H), 7.01 – 6.95 (m, 2H), 6.33 (s, 1H), 6.07 (d, J = 5.6 Hz, 2H), 4.32 – 4.22 (m, 4H), 3.06 (d, J = 14.4 Hz, 1H), 2.91 (d, J = 14.4 Hz, 1H), 1.30 (td, J = 7.2, 2.0 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.9, 169.9, 169.2, 163.1 (d, JC-F = 247.5 Hz), 158.2, 143.9, 131.7, 129.3 (d, JC-F = 8.3 Hz), 128.6 (d, JC-F = 3.4 Hz), 121.3, 115.7, 115.5, 97.5, 63.2, 62.6, 62.2, 41.7, 14.1. 19F NMR (376 MHz, CDCl3) δ = -112.0 (s, 1F). HRMS (ESI, TOF) (m/z): Calculated for C20H20FO6 (M + H)+: 375.1244, Found: 375.1244. Diethyl 9-(4-chlorophenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3ea). Yellow liquid, 100.7 mg, 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 4.2 Hz, 1H), 7.28 – 7.25 (m, 2H), 7.23 – 7.18 (m, 2H), 6.36 (s, 1H), 6.07 (d, J = 5.6 Hz, 1H), 4.34 – 4.19 (m, 4H), 3.06 (d, J = 14.4 Hz, 1H), 2.91 (d, J = 14.4 Hz, 1H), 1.30 (td, J = 7.2, 2.0 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.9, 169.9, 169.1, 158.1, 143.8, 135.1, 132.2, 131.0, 128.9, 128.7, 121.4, 97.4, 63.3, 62.7, 62.3, 41.8, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C20H20O6Cl (M + H)+: 391.0948, Found: 391.0957. Diethyl 9-(4-bromophenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3fa). Yellow liquid, 111.3 mg, 85% yield. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 5.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.35 (s, 1H), 6.34 (d, J = 5.6 Hz, 1H), 4.31 – 4.17 (m, 4H), 3.03 (d, J = 14.4 Hz, 1H), 2.88 (d, J = 14.4 Hz, 1H), 1.27 (td, J = 7.2, 2.0 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.8, 169.8, 169.1, 158.0, 143.8, 132.2, 131.8, 131.4, 128.9, 123.3, 121.4, 97.3, 63.3, 62.7, 62.3, 41.8, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C20H23BrNO6 (M + NH4)+: 452.0709, Found: 452.0712. Diethyl 9-(4-cyanophenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3ga). Yellow liquid, 57.8 mg, 51% yield. 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.51 (m, 2H), 7.49 (d, J = 5.6 Hz, 2H), 7.40 – 7.32 (m, 2H), 6.46 (s, 1H), 6.09 (d, J = 5.2 Hz, 2H), 4.32 – 4.20 (m, 4H), 3.06 (d, J = 14.4 Hz, 1H), 2.91 (d, J = 14.4 Hz, 1H), 1.31 (td, J = 7.2, 1.6 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.6, 169.6, 168.8, 157.7, 143.3, 137.1, 134.2, 132.4, 128.1, 121.7, 118.3, 112.8, 97.2, 63.5, 62.9, 62.5, 41.9, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C21H20NO6 (M + H)+: 382.1291, Found: 382.1305. Diethyl 9-(4-(methoxycarbonyl)phenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3ha). Yellow liquid, 64.5 mg, 52% yield. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 6.4 Hz, 2H), 7.48 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 6.8 Hz, 2H), 6.43 (s, 1H), 6.06 (d, J = 5.6 Hz, 2H), 4.31 – 4.19 (m, 4H), 3.87 (s, 3H), 3.05 (d, J = 14.4 Hz, 1H), 2.90 (d, J = 14.4 Hz, 1H), 1.28 (t, J = 7.2 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.8, 169.7, 169.0, 166.5, 158.0, 144.0, 137.0, 133.2, 130.5, 129.8, 127.4, 121.5, 97.4, 63.4, 62.7,



Page 12 of 16

62.3, 52.3, 41.9, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C22H23O8 (M + H)+: 415.1393, Found: 415.1403. Diethyl

2-oxo-9-(4-(trifluoromethyl)phenyl)-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate

(3ia).

Yellow liquid, 108.9 mg, 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 6.44 (s, 1H), 6.09 (d, J = 5.6 Hz, 2H), 4.34 – 4.22 (m, 4H), 3.08 (d, J = 14.4 Hz, 1H), 2.93 (d, J = 14.4 Hz, 1H), 1.31 (td, J = 7.2, 2.4 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.7, 169.7, 168.9, 157.8, 143.7, 136.1, 133.5, 130.9 (q, JC-F = 32.4 Hz), 127.8, 125.5 (q, JC-F = 3.7 Hz), 123.9 (d, JC-F = 270.5 Hz), 121.5, 97.3, 63.4, 62.8, 62.3, 41.8, 14.0. 19F NMR (376 MHz, CDCl3) δ = -62.9 (s, 3F). HRMS (ESI, TOF) (m/z): Calculated for C21H20F3O6 (M + H)+: 425.1212, Found: 425.1221. Diethyl 9-(2-fluorophenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3ja). Yellow liquid, 94.7 mg, 84% yield. 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 5.6, 1.6 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.25 – 7.21 (m, 1H), 7.10 – 7.00 (m, 2H), 6.41 (d, J = 1.2 Hz, 2H), 5.98 (d, J = 5.6 Hz, 1H), 4.31 – 7.25 (m, 1H), 3.11 (d, J = 14.4 Hz, 1H), 2.87 (d, J = 14.4 Hz, 1H), 1.31 (td, J = 7.2, 0.8 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.8, 169.6, 169.1, 159.8 (d, JC-F = 246.8 Hz), 157.4, 138.2, 135.4 (d, JC-F = 3.9 Hz), 130.5 (d, JC-F = 8.3 Hz), 130.2 (d, JC-F = 2.5 Hz), 124.1 (d, JC-F = 3.7 Hz), 121.1, 119.8 (d, JC-F = 14.9 Hz), 115.8, 115.6, 98.0,

64.0, 62.6, 62.2, 40.9, 14.0 (d, JC-F = 2.5 Hz). 19F NMR (376 MHz, CDCl3) δ = -113.2 (s, 1F). HRMS (ESI, TOF) (m/z): Calculated for C20H20FO6 (M + H)+: 375.1244, Found: 375.1241. Diethyl 9-(3-fluorophenyl)-2-oxo-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3ka). Yellow liquid, 97.8 mg, 87% yield. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 5.2 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.06 – 6.95 (m, 3H), 6.39 (s, 1H), 6.09 (d, J = 5.6 Hz, 1H), 4.32 – 4.22 (m, 4H), 3.06 (d, J = 14.4 Hz, 1H), 2.91 (d, J = 14.4 Hz, 1H), 1.30 (td, J = 7.2, 1.2 Hz, 6H) 13C {1H} NMR (100 MHz, CDCl3) δ 171.8, 169.8, 169.1, 162.6 (d, JC-F = 245.3 Hz), 158.0, 143.7 (d, JC-F =2.4 Hz), 134.5 (d, JC-F =8.0 Hz), 132.7, 130.3 (d, JC-F =8.4 Hz), 123.1 (d, JC-F =3.0 Hz), 121.4, 116.0 (d, JC-F =20.9 Hz), 114.5 (d, JC-F =22.4 Hz), 97.3, 63.3, 62.7, 62.3, 41.8, 14.1. 19F NMR (376 MHz, CDCl3) δ = -112.2 (s, 1F). HRMS (ESI, TOF) (m/z): Calculated for C20H20FO6 (M + H)+: 375.1244, Found: 375.1246. Diethyl 2-oxo-9-(m-tolyl)-1-oxaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3la). Yellow liquid, 98.7 mg, 89% yield. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 5.2 Hz, 1H), 7.20 – 7.02 (m, 4H), 6.34 (s, 1H), 6.06 (d, J = 5.2 Hz, 1H), 4.32 – 4.21 (m, 4H), 3.05 (d, J = 14.4 Hz, 1H), 2.91 (d, J = 14.4 Hz, 1H), 2.31 (s, 3H), 1.30 (td, J = 7.2, 2.8 Hz, 6H).

13

C {1H} NMR (100 MHz, CDCl3) δ 172.0, 170.0,

169.3, 158.3, 144.9, 138.2, 132.4, 131.5, 129.7, 128.4, 128.1, 124.2, 121.2, 97.6, 63.2, 62.5, 62.1, 41.8, 21.4,


Page 13 of 16 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


14.1. HRMS (ESI, TOF) (m/z): Calculated for C21H23O6 (M + H)+: 371.1495, Found: 371.1495. Diethyl 4-(2-fluorophenyl)-8-oxospiro[4.5]deca-3,6,9-triene-2,2-dicarboxylate (3ma). Yellow liquid, 60.7 mg, 58% yield. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 5.2 Hz, 1H), 6.06 (d, J = 5.6 Hz, 1H), 5.87 (t, J = 2.0 Hz, 1H), 4.24 – 4.14 (m, 4H), 2.90 (d, J = 14.4 Hz, 1H), 2.68 (d, J = 14.4 Hz, 1H), 1.91 – 1.82 (m, 1H), 1.74 – 1.65 (m, 1H), 1.49 – 1.39 (m, 2H), 1.29 – 1.23 (m, 10H), 0.84 (t, J = 6.8 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.3, 170.5, 169.7, 157.8, 146.8, 128.1, 120.9, 98.2, 63.7, 62.3, 62.0, 40.6, 31.5, 27.2, 25.5, 22.4, 14.08, 14.07, 14.0. HRMS (ESI, TOF) (m/z): Calculated for C19H30NO6 (M + NH4)+: 368.2073, Found: 368.2071. Diethyl 4-butyl-8-oxospiro[4.5]deca-3,6,9-triene-2,2-dicarboxylate (3na). Yellow liquid, 37.5 mg, 33% yield. 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.83 (m, 2H), 7.62 – 7.57 (m, 2H), 7.49 – 7.45 (m, 2H), 6.70 (s, 1H), 6.14 (d, J = 5.6 Hz, 1H), 4.35 – 4.15 (m, 4H), 3.10 (d, J = 14.4 Hz, 1H), 2.83 (d, J = 14.4 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).

13

C {1H} NMR (100 MHz, CDCl3) δ 190.8, 171.9, 168.51,

168.49, 157.3, 142.9, 142.2, 137.0, 133.8, 129.7, 128.8, 120.5, 96.1, 64.6, 63.1, 62.8, 41.3, 14.14, 14.08. HRMS (ESI, TOF) (m/z): Calculated for C21H21O7 (M + H)+: 385.1287, Found: 385.1288. 2,2-Diethyl 3-methyl 8-oxospiro[4.5]deca-3,6,9-triene-2,2,3-tricarboxylate (3oa). Yellow liquid, 46.7 mg, 44% yield. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 5.6 Hz, 1H), 6.31 (s, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.27 – 4.14 (m, 4H), 2.85 (d, J = 14.4 Hz, 1H), 2.68 (d, J = 14.4 Hz, 1H), 1.26 (td, J = 7.2, 1.6 Hz, 6H), 0.07 (s, 9H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.0, 169.5, 168.9, 159.0, 148.3, 142.9, 119.9, 101.2, 66.7, 62.1, 61.8, 41.7, 13.78, 13.76, -1.1. HRMS (ESI, TOF) (m/z): Calculated for C17H25O6Si (M + H)+: 353.1420, Found: 353.1418. Diethyl 3-benzoyl-8-oxospiro[4.5]deca-3,6,9-triene-2,2-dicarboxylate (3pa). Yellow liquid, 20.7 mg, 19% yield. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 5.6 Hz, 1H), 7.31 – 7.28 (m, 2H), 7.10 – 7.06 (m, 2H), 5.89 (d, J = 5.6 Hz, 1H), 4.29 (p, J = 6.8 Hz, 4H), 3.06 (d, J = 14.4 Hz, 1H), 2.86 (d, J = 14.4 Hz, 1H), 1.88 (s, 3H), 1.32 (td, J = 7.2, 6.4 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.1, 170.3, 169.4, 157.3, 140.9, 140.2, 132.6, 129.1, 128.5, 128.3, 121.5, 97.9, 66.7, 62.4, 62.1, 41.6, 14.24, 14.18, 13.95. HRMS (ESI, TOF) (m/z): Calculated for C21H23O6 (M + H)+: 371.1495, Found: 371.1486. Diethyl 8-oxo-4-(trimethylsilyl)spiro[4.5]deca-3,6,9-triene-2,2-dicarboxylate (3qa). Yellow liquid, 67.3 mg, 62% yield. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 4.2 Hz, 1H), 7.24 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 3.2 Hz, 1H), 6.94 (dd, J = 4.2, 3.6 Hz, 1H), 6.40 (s, 1H), 6.14 (d, J = 5.6 Hz, 1H), 4.30 – 4.19 (m, 4H), 3.04 (d, J = 14.4 Hz, 1H), 2.87 (d, J = 14.4 Hz, 1H), 1.28 (t, J = 6.8 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ



172.0, 169.8, 169.2, 158.2, 138.3, 133.6, 129.3, 127.7, 126.7, 126.3, 121.5, 97.0, 63.4, 62.7, 62.3, 41.6, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C18H19O6S (M + H)+: 363.0902, Found: 363.0910. Diethyl 3-methyl-8-oxo-4-phenylspiro[4.5]deca-3,6,9-triene-2,2-dicarboxylate (3ra). Yellow liquid, 77.9 mg, 72% yield. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 5.6 Hz, 1H), 7.25 – 7.24 (m, 1H), 7.16 (dd, J = 2.8, 1.2 Hz, 1H), 7.09 (dd, J = 4.2, 1.6 Hz, 1H), 6.37 (s, 1H), 6.11 (d, J = 5.6 Hz, 1H), 4.29 – 4.18 (m, 4H), 3.02 (d, J = 14.4 Hz, 1H), 2.86 (d, J = 14.4 Hz, 1H), 1.27 (t, J = 7.2 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.2, 169.9, 169.3, 158.7, 139.5, 132.6, 129.9, 126.7, 126.1, 123.2, 121.0, 97.3, 63.2, 62.6, 62.2, 41.6, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C18H19O6S (M + H)+: 363.0902, Found: 363.0910. Ethyl 7-acetyl-2-oxo-9-phenyl-1-oxaspiro[4.4]nona-3,8-diene-7-carboxylate (3ad). Yellow liquid, 65.7 mg, 67% yield as a mixture of syn- and anti-isomer. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 5.6 Hz, 1H), 7.40 (d, J = 5.6 Hz, 1H), 7.32 - 7.28 (m 5H), 7.27 - 7.23 (m 5H), 6.43 (s, 1H), 6.41 (s, 1H), 6.09 (d, J = 5.6 Hz, 1H), 6.06 (d, J = 5.6 Hz, 1H), 4.32 - 4.29 (m 2H), 4.28 - 4.23 (m 2H), 3.10 (d, J = 5.6 Hz, 1H), 3.07 (d, J = 5.6 Hz, 1H), 2.83 (d, J = 14.4 Hz, 1H), 2.77 (d, J = 14.4 Hz, 1H), 2.333 (s, 3H), 2.326 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 202.2, 201.2, 172.1, 171.9, 170.1, 170.0, 158.0, 157.9, 145.2, 145.1, 132.5, 132.2, 131.2, 129.11, 129.07, 128.68, 128.64, 127.3, 127.2, 121.6, 121.2, 97.6, 97.5, 70.3, 69.8, 62.6, 62.4, 40.8, 40.3, 27.1, 27.0, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C19H18O5Na (M + Na)+: 349.1052, Found: 349.1039. Diethyl 2-oxo-9-phenyl-1-thiaspiro[4.4]nona-3,8-diene-7,7-dicarboxylate (3af). Yellow liquid, 44.7 mg, 40% yield. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 6.0 Hz, 1H), 7.37 - 7.27 (m 5H), 6.31 (s, 1H), 6.27 (d, J = 6.0 Hz, 1H), 4.31 - 4.23 (m 4H), 3.24 (d, J = 14.8 Hz, 1H), 3.15 (d, J = 14.4 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 198.9, 169.9, 169.7, 161.5, 146.4, 133.3, 131.7, 129.8, 129.1, 128.5, 127.1, 72.9, 64.6, 62.5, 62.4, 45.7, 14.1. HRMS (ESI, TOF) (m/z): Calculated for C20H21O5S (M + H)+: 373.1110, Found: 373.1096. Procedure for 4 mmol-Scale Reaction of 1a and 2a. To a 100 mL dried Schlenk flask equipped with a magnetic stir bar was added 1a (408.5 mg, 4.00 mmol), 2a (3.18 g, 8.0 mmol), fac-Ir(ppy)3 (56.0 mg, 0.04 mmol). Then 67 mL mixed solvent (CH3CN:H2O=8:1) was added into the reaction tube via a syringe. The resulting mixture was degassed by the freeze-pump-thaw method and then stirred at a distance of ~5 cm from a 7 W blue LED bulb at room temperature for 12 h. After the completion of the reaction, the mixture was concentrated and the pure product 3aa was obtained in 79% yield (1.13 g) by flash chromatography on silica-gel (PE / EA = 5:1).


Page 14 of 16

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SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website. NMR spectra (PDF)

ACKNOWLEDGMENT We thank the National Natural Science Foundation of China for the financial support.

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Cyclization

of

2-Bromo-1,3-dicarbonyl

Compounds

and

Alkynes:

Synthesis

of

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Visible-Light-Induced Intermolecular Dearomative Cyclization of

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