Synthesis of gem-difluoromethylenated spiro-γ-butyrolactones by employing PhSCF2Si(CH3)3 as a gem-difluoromethylenating agent

Job/Unit: O30998

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Date: 12-09-13 17:13:17

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FULL PAPER

DOI: 10.1002/ejoc.201300998

Synthesis of gem-Difluoromethylenated Spiro-γ-butyrolactones by Employing

PhSCF₂Si(CH₃)₃as a gem-Difluoromethylenating Agent

Adisak Chatupheeraphat,^[a]Darunee Soorukram,^[a]Chutima Kuhakarn,^[a]

Patoomratana Tuchinda,^[a]Vichai Reutrakul,^[a]Chaveng Pakawatchai,^[b]

Saowanit Saithong,^[b]and Manat Pohmakotr*^[a]

Keywords: Lactones / Difluoromethylenation / Cyclization / Fluorine

PhSCF₂TMS was utilized as a useful gem-difluoromethylene

building block for the synthesis of gem-difluoromethylenated

spiro-γ-butyrolactones. The radical cyclization of γ-alkenyl-

γ-gem-difluoro(phenylsulfanyl)methyl-γ-butyrolactones pro-

vided gem-difluoromethylenated spiro-γ-butyrolactones.

magnesium bromides followed by esterification. Alterna-

tively, the key compounds 3 should also be derived from γ-

Introduction

Fluorine-containing organic molecules are important gem-difluoro(phenylsulfanyl)methylated γ-butyrolactones 4,

structural motifs in a number of drug candidates, agro- which could be prepared by the fluoride-catalyzed nucleo-

chemical reagents, and functional materials.^[1]Their unique philic addition of 1 with phthalic anhydride. The treatment

properties stem from the enhanced chemical, physical, and of 4 with alkenylmagnesium bromides followed by lactoni-

metabolic stability of the fluorinated moiety. Accordingly, zation gave the key intermediates 3. Notably, the function-

there has been great interest in the syntheses of fluorine- alized cyclopentanes and cyclohexanes bearing a spiro-γ-

containing natural product analogs and materials.^[2]Despite

this interest, general synthetic methods for the introduction

of the gem-difluoromethylene group into organic com-

pounds are still highly desirable. Among several fluorinated

reagents, PhSCF₂TMS (1; TMS = trimethylsilyl), first intro-

duced by Prakash and co-workers, has gained popularity

as a useful and convenient gem-difluoromethylene building

block.^[3]In connection with our work on the synthesis of

fluorine-containing organic molecules by using 1 as a gem-

difluoromethylene radical anion equivalent (CF₂^·–),^[4]we re-

port herein a synthetic strategy to gem-difluoromethyl-

enated spiro-γ-butyrolactones. It was envisaged that the

gem-difluoromethylenated spiro-γ-butyrolactones 5 could

be derived from the key intermediates 3 by an intramolecu-

lar radical cyclization (Scheme 1). Compounds 3 should be

obtained by sequential chemoselective fluoride-catalyzed

nucleophilic addition of 1 and lactonization of γ-keto esters

2, prepared by treatment of succinic anhydride with alkenyl-

[a] Department of Chemistry and Center of Excellence for

Innovation in Chemistry, Faculty of Science, Mahidol

University,

Rama VI Road, Bangkok 10400, Thailand

E-mail: manat.poh@mahidol.ac.th

http://chemistr y .sc.mahidol.ac.th

[b] Department of Chemistry and Center of Excellence for

Innovation in Chemistry, Faculty of Science, Prince of Songkla

University,

Hat Yai, Songkla 90112, Thailand

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300998.

Scheme 1. Proposed synthetic route to gem-difluoromethylenated

spiro-γ-butyrolactones.

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butyrolactone moiety have been found in natural products 1.5 equiv.) led to an improved yield of 3a (75%, Table 1,

that exhibit potential bioactivities.^[5]Therefore, there has Entry 3). Fortunately, the reaction with 1.2 equivalents of 1

been considerable interest in the development of efficient in THF at –78 °C for 3.5 h gave an excellent yield of 3a

methods for the syntheses of spiro-γ-butyrolactones.^[6]

(92%) along with 6 (1%) (Table 1, Entry 4). Under the opti-

mized reaction conditions (Table 1, Entry 4), the reaction

of 2aЈ readily proceeded to yield the expected γ-butyro-

lactone 3a in 97% yield as a single product (Table 1, En-

try 5). Under similar reaction conditions, keto esters 2b–d

afforded γ-gem-difluoro(phenylsulfanyl)methyl-γ-butyro-

lactones 3b–d in high yields (93–94%) after lactonization.

The reactions are summarized in Scheme 3.

Results and Discussion

Preparation of 3 from Succinic Anhydride

To begin with, the requisite γ-keto esters 2a and 2aЈ were

prepared in good yields by treatment of succinic anhydride

with homoallylmagnesium bromide (2 equiv.) in the pres-

ence of a catalytic amount of CuI^[7]at –20 °C followed by

esterification of the resulting ketocarboxylic acid with a

mixture of SOCl₂/MeOH or SOCl₂/EtOH at –10 °C to

room temp. for 2 h. The olefin cross-metathesis of 2aЈ with

styrene derivatives mediated by the 2nd generation Grubbs

catalyst (2.5 mol-%) in CH₂Cl₂at reflux gave keto esters

2b–d as E isomers (Scheme 2).

Table 1. Fluoride-catalyzed nucleophilic addition of 1 to γ-keto es-

ters 2 under various conditions.

Entry

2

Catalyst

1

T

[°C]

Time

3a

6

[equiv.]

[h] (% yield)^[a](% yield)^[a]

1

2

3

4

5

2a TBAF

2a TBAT

2a TBAF

2aЈ TBAF

2

1.5

1.2

–78 to r.t.

–78

5

3.5

3

46

31

75

92

97

49

51

17

1

–78

–

Scheme 2. Preparation of γ-keto esters 2.

[a] Yield of isolated product.

We initially screened for the optimized conditions for

chemoselective fluoride-catalyzed nucleophilic addition of 1

with γ-keto ester 2a.^[4d]The treatment of 1 (2 equiv.) with

2a in the presence of 10 mol-% of tetrabutylammonium

fluoride (TBAF) in tetrahydrofuran (THF) at –78 °C to

room temp. for 5 h followed by lactonization [pTsOH (cat.),

CH₂Cl₂, room temp.] gave the expected γ-butyrolactone 3a

in 46% yield together with 6 in 49% yield (Table 1, En-

try 1). The formation of 3a can be explained by the chemo-

selective fluoride-catalyzed nucleophilic addition of 1 to the

keto group of 2a followed by lactonization under acidic

treatment of the firstly formed γ-hydroxy ester adduct. The

undesired adduct 6 was believed to derive from the nonse-

lective fluoride-catalyzed addition of 1 to both of the keto

and the ester groups of 2a followed by lactol formation

upon acidic workup. A similar result was observed when

Scheme 3. Fluoride-catalyzed nucleophilic addition of 1 to γ-keto

esters 2b–d.

Preparation of 3 from Phthalic Anhydride

γ-Lactol 4 was readily prepared in good yield (88%) by

tetrabutylammonium triphenyldifluorosilicate (TBAT) was the TBAT-catalyzed nucleophilic addition of 1 (2 equiv.) to

employed in place of TBAF (Table 1, Entry 2). The re- phthalic anhydride (Scheme 4) according to our previous

duction of the amount of 1 employed (from 2 equiv. to report.^[3a]Primarily, the treatment of 4 with homoallylmag-

2

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Synthesis of gem-Difluoromethylenated Spiro-γ-butyrolactones

nesium bromide (5 equiv.) at –10 °C for 0.5 h gave the ex- Preparation of gem-Difluoromethylenated Spiro-γ-

pected product 3e (27% yield) along with 7 (53%) after lact- butyrolactones 5

onization. An improved yield of 3e (52% yield) was

Having achieved the preparation of γ-difluoro(phenyl-

achieved when the reaction with the Grignard reagent was

sulfanyl)methyl-γ-butyrolactones 3 and 8, which are the key

performed at –78 °C for 3 h. However, a significant amount

intermediates for the syntheses of the desired γ-(gem-di-

of 7 was also isolated (31% yield). In the presence of an

fluoromethylenated) spiro-γ-butyrolactones, we next investi-

additive, tetrabutylammonium bromide (TBAB, 5 equiv.),

gated an intramolecular radical cyclization (Table 2). Thus,

homoallylmagnesium bromide reacted with 4 at –78 °C for

the exposure of 3a–d to Bu₃SnH in the presence of a cata-

3 h to provide 3e (62% yield) and 7 (23% yield).^[8]Under

similar reaction conditions, compounds 8a and 7 were ob-

tained in 58 and 29% yields, respectively, from the reaction

Table 2. Preparation of gem-difluoromethylenated spiro-γ-butyro-

of 4 with 1-pentenylmagnesium bromide. The formation of lactones 5 by intramolecular radical cyclization of 3 and 8.

7 could be rationalized by competitive reduction of the in-

termediate 4A owing to a β-hydrogen transfer from the

Grignard reagent during the reaction.

Scheme 4. Preparation of 3e and 8a from phthalic anhydride.

With compounds 3e and 8a in hand, we used them to

prepare the alkenyl-substituted compounds 3f–h and 8b–e

in good yields through olefin cross-metathesis, as summa-

rized in Scheme 5. Except for 8e, the alkenyl-substituted

compounds were obtained as mixtures of E and Z isomers

with the E isomer as the major isomer.

Scheme 5. Synthesis of 3f–h and 8b–e by olefin cross-metathesis of

3e and 8a with styrene derivatives.

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Table 2. (continued)

form the expected gem-difluoromethylenated spiro-γ-

butyrolactones 5e–m. The results are summarized in

Table 2.

The relative stereochemistry of 5dA and 5iA were as-

signed on the basis of X-ray crystallography (Figure 1).^[9]

Therefore, we speculate that the relative stereochemistries

of 5aA–5cA and 5jA–5lA are similar to those of 5dA and

5iA.

Conclusions

In conclusion, we have developed a synthetic entry to

gem-difluoromethylenated spiro-γ-butyrolactones by em-

ploying PhSCF₂TMS (1) as a “CF₂^·–” building block. The

present method proves potentially useful as a general syn-

thetic entry to gem-difluoromethylenated spiro-γ-butyro-

lactones, which are versatile building blocks for the synthe-

sis of natural products containing spiro-γ-butyrolactone

moieties.

Experimental Section

General: All reactions were performed under an argon atmosphere,

and glassware, needles, and syringes were oven-dried and then kept

in a desiccator before use. THF was distilled from sodium–benzo-

phenone ketyl. Dichloromethane, toluene, and ethanol were dis-

tilled from calcium hydride and stored over activated molecular

sieves (4 Å). Methanol was distilled from Mg turnings. Column

chromatography was performed by using Merck silica gel 60 PF₂₅₄

(Art 7736). Other common solvents [hexanes, ethyl acetate

(EtOAc), and acetone] were distilled before use. The ¹H NMR spec-

tra were recorded with a Bruker DPX-300 (300 MHz), Bruker-400

(400 MHz), or Bruker-500 (500 MHz) spectrometer with samples

in CDCl₃and tetramethylsilane as an internal standard. The ¹³C

NMR spectra were recorded with a Bruker DPX-300 (75 MHz),

Bruker-400 (100 MHz), or Bruker-500 (125 MHz) spectrometer

with samples in CDCl₃and residual non-deuterated solvent peaks

as an internal standard. The ¹⁹F NMR spectra were recorded with

a Bruker-400 (376 MHz) or a Bruker-500 (470 MHz) spectrometer,

and chemical shifts (δ) were measured with trichlorofluoromethane

(δ = 0 ppm) as an internal standard. The IR spectra were recorded

with either a Jasco A-302 or a Perkin–Elmer 683 infrared spectro-

meter. The mass spectra were recorded by using a Thermo Finni-

gan Polaris Q mass spectrometer. The high-resolution mass spectra

were recorded with either an HR-TOF-MS Micromass model VQ-

TOF2 or Finnigan MAT 95 mass spectrometer. Melting points

were recorded with a Buchi 501 melting point apparatus. The X-

ray crystallographic analysis was performed with a Bruker SMART

APEX CCD diffractometer.

[a] Isolated yield; a small amount of its diastereomer is included,

see Supporting Information. [b] Isolated yield of pure diastereomer.

[c] Isolated yield of a mixture of diastereomers. [d] The ratio of

diastereoisomers was determined by ¹⁹F NMR spectroscopy of the

crude mixture.

4-Oxooct-7-enoic Acid: To a suspension of magnesium turnings

(6.5 g, 268 mmol) in dry THF (80 mL) was slowly added a solution

of homoallyl bromide (8.1 mL, 80 mmol) in dry THF (80 mL) with

a cannula over a period of 1 h at room temperature. The reaction

mixture was stirred at room temperature for 2 h. The resulting

Grignard reagent was then added dropwise over a period of 30 min

to a suspension of succinic anhydride (4 g, 40 mmol) and copper

iodide (1.1 g, 6 mmol) in dry THF (40 mL) at –20 °C. The reaction

mixture was stirred at –20 °C and then warmed to 0 °C for 3 h.

The reaction mixture was quenched with HCl (2 m, 20 mL) at 0 °C

lytic amount of azobisisobutyronitrile (AIBN) in toluene at

reflux overnight yielded the expected γ-(gem-difluorometh-

ylenated) spiro-γ-butyrolactones 5a–d in good yields (68–

83%) as mixtures of two diastereomers, which could be

chromatographically separated.

Under similar reaction conditions, the radical cycliza-

tions of 3e–h and 8a–e were achieved without difficulty to and extracted with EtOAc (4ϫ 50 mL). The combined organic

4

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Synthesis of gem-Difluoromethylenated Spiro-γ-butyrolactones

Figure 1. X-ray crystallographic structures of 5dA and 5iA.

phase was washed with brine (50 mL) and dried with anhydrous

Na₂SO₄. After removal of the solvent, the crude product was puri-

fied by column chromatography (SiO₂, 30% EtOAc/0.5% AcOH in

hexanes) to afford 4-oxooct-7-enoic acid (3.7 g, 59%) as a pale yel-

umn chromatography (SiO₂, 20% EtOAc in hexanes) to give 2a

(713 mg, 93% yield) as a colorless liquid. FTIR (CHCl ): ν = 1733,

˜

3

1719, 1439, 1411, 1365, 1178, 919 cm^–1. ¹H NMR (300 MHz,

CDCl₃): δ = 5.73 (ddt, J = 16.7, 12.9, 6.5 Hz, 1 H, CH₂=CH),

5.02–4.85 (m, 2 H, CH₂=CH), 3.60 (s, 3 H, OCH₃), 2.73–2.64 (m,

2 H, CH₂), 2.58–2.43 (m, 4 H, 2ϫ CH₂), 2.30–2.20 (m, 2 H, CH₂)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 208.0 (C), 173.2 (C), 136.9

(CH), 115.2 (CH₂), 51.7 (CH₃), 41.7 (CH₂), 37.0 (CH₂), 27.6 (2ϫ

low viscous oil. FTIR (CHCl ): ν = 3029, 1713, 1404, 1368, 1286,

˜

3

1256, 920 cm^–1. H NMR (300 MHz, CDCl₃): δ = 10.58–8.80 (br,

1

1 H, OH), 5.79 (ddt, J = 16.7, 12.9, 6.4 Hz, 1 H, CH₂=CH), 5.09–

4.90 (m, 2 H, CH₂=CH), 2.75–2.68 (m, 2 H, CH₂), 2.67–2.59 (m,

2 H, CH₂), 2.58–2.50 (m, 2 H, CH₂), 2.40–2.27 (m, 2 H, CH₂) ppm. CH₂) ppm. MS: m/z (%) = 171 (100) [M + H]⁺, 169 (18), 159 (4),

¹³C NMR (75 MHz, CDCl₃): δ = 208.0 (C), 178.7 (C), 136.8 (CH), 115 (13), 111 (20), 95 (25), 93 (2). HRMS (ESI-TOF): calcd. for

115.3 (CH₂), 41.7 (CH₂), 36.8 (CH₂), 27.7 (CH₂), 27.6 (CH₂) ppm. C₉H₁₄O₃Na [M + Na]⁺193.0841; found 193.0840.

MS: m/z (%) = 157 (100) [M + H]⁺, 139 (7), 111 (34), 95 (32), 55

(2). HRMS (ESI-TOF): calcd. for C₈H₁₂O₃Na [M

179.0684; found 179.0688.

+

Na]⁺

Ethyl 4-Oxooct-7-enoate (2aЈ): According to general procedure A,

a mixture of 4-oxooct-7-enoic acid (1.6 g, 10 mmol) in dry EtOH

(50 mL) and thionyl chloride (2.5 mL, 30 mmol) gave 2aЈ (1.52 g,

82% yield) as a colorless liquid after purification by column

General Procedure A for the Preparation of Keto Esters 2

Methyl 4-Oxooct-7-enoate (2a): A solution of 4-oxooct-7-enoic acid

(704 mg, 4.5 mmol) in dry MeOH (20 mL) was treated with thionyl

chloride (0.8 mL, 11 mmol) at –10 °C, and the mixture was slowly

warmed to room temperature for 2 h. The reaction mixture was

quenched with saturated Na₂CO₃(10 mL), and the resulting mix-

ture was evaporated and extracted with EtOAc (3ϫ 20 mL). The

combined organic phase was washed successively with water

(10 mL) and brine (10 mL) and dried with anhydrous Na₂SO₄. Af-

ter removal of the solvent, the crude product was purified by col-

chromatography (SiO , 20% EtOAc in hexanes). FTIR (CHCl ): ν

˜

2 3

= 1718, 1412, 1376, 1351, 1096, 919 cm^–1. ¹H NMR (300 MHz,

CDCl₃): δ = 5.78 (ddt, J = 16.7, 12.9, 6.5 Hz, 1 H, CH₂=CH),

5.07–4.90 (m, 2 H, CH₂=CH), 4.10 (q, J = 7.2 Hz, 2 H, OCH₂),

2.75–2.63 (m, 2 H, CH₂), 2.61–2.48 (m, 4 H, 2ϫ CH₂), 2.40–2.20

(m, 2 H, CH₂), 1.22 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 208.1 (C), 172.7 (C), 136.9 (CH), 115.2

(CH₂), 60.5 (CH₂), 41.7 (CH₂), 37.0 (CH₂), 27.9 (CH₂), 27.6 (CH₂),

14.1 (CH₃) ppm. MS: m/z (%) = 185 (100) [M + H]⁺, 129 (4), 111

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(16), 95 (18). HRMS (ESI-TOF): calcd. for C₁₀H₁₆O₃Na [M +

Na]⁺207.0997; found 207.1003.

152 (34), 141 (21), 129 (15), 115 (8), 101 (26). HRMS (ESI-TOF):

calcd. for C₂₀H₂₂O₃Na [M + Na]⁺333.1467; found 333.1467.

General Procedure B for the Preparation of Keto Esters 2b–d

General Procedure C for the Preparation of γ-(Difluorophenylsulf-

anylmethyl)-γ-butyrolactones 3

(E)-Ethyl 4-Oxo-8-phenyloct-7-enoate (2b): A solution of 2aЈ (1.9 g,

10 mmol) and styrene (4.5 mL, 40 mmol) in dry CH₂Cl₂(40 mL)

was treated with a catalytic amount of Grubbs’ 2^ndgeneration cata-

lyst (212 mg, 0.3 mmol) in CH₂Cl₂(10 mL). The reaction mixture

was heated to reflux overnight. After completion of the reaction,

the solvent was evaporated, and the crude product was purified by

column chromatography (SiO₂, 100% hexanes to 10% EtOAc in

hexanes) to give 2b (1.6 g, 62% yield) as a pale yellow viscous oil.

γ-[Difluoro(phenylsulfanyl)methyl]-γ-(butyl-3-ene)-γ-butyrolactone

(3a): A solution of 1 (241 mg, 1 mmol) and 2a (92 mg, 0.5 mmol)

in dry THF (1 mL) was treated with 10 mol-% TBAF solution

(0.25 mL, 0.1 mmol, 0.4 m solution in dry THF) at –78 °C, and the

mixture was slowly warmed to room temperature for 5 h. The reac-

tion was quenched at room temperature with excess TBAF solu-

tion, and the resulting mixture was stirred at room temperature for

15 min, diluted with water (10 mL), and then extracted with EtOAc

(3ϫ 10 mL). The combined organic phase was washed successively

with water (10 mL) and brine (10 mL) and dried with anhydrous

Na₂SO₄. After removal of the solvent, the crude product was

treated with a catalytic amount of pTsOH in CH₂Cl₂(2 mL). The

reaction mixture was stirred at room temperature overnight. After

removal of the solvent, water (10 mL) was added, and the mixture

was extracted with EtOAc (4 ϫ 10 mL). The combined organic

phase was washed with water (15 mL) and brine (15 mL) and dried

with anhydrous Na₂SO₄. The crude product was purified by col-

umn chromatography (SiO₂, 10% EtOAc in hexanes) to give 3a

(68 mg, 46% yield) as a white solid [m.p. 44–45 °C (hexanes)] and

6 (119 mg, 49% yield) as a white solid [m.p. 90–92 °C (CH₂Cl₂/

FTIR (CHCl ): ν = 1721, 1447, 1412, 1376, 1350, 1192, 1097,

˜

3

966 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.40–7.26 (m, 4 H, 4ϫ

ArH), 7.25–7.16 (m, 1 H, ArH), 6.42 (d, J = 15.9 Hz, 1 H,

CH=CH), 6.21 (dt, J = 15.9, 6.7 Hz, 1 H, CH=CH), 4.15 (q, J =

7.2 Hz, 2 H, OCH₂), 2.83–2.71 (m, 2 H, CH₂), 2.71–2.58 (m, 4 H,

2ϫ CH₂), 2.58–2.46 (m, 2 H, CH₂), 1.27 (t, J = 7.2 Hz, 3 H, CH₃)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 208.0 (C), 172.7 (C), 137.3

(C), 130.7 (CH), 128.7 (CH), 128.4 (2ϫ CH), 127.0 (CH), 125.9

(2ϫ CH), 60.6 (CH₂), 42.2 (CH₂), 37.1 (CH₂), 27.9 (CH₂), 27.0

(CH₂), 14.1 (CH₃) ppm. MS: m/z (%) = 261 (100) [M + H]⁺, 259

(11), 215 (3), 169 (4), 117 (3). HRMS (ESI-TOF): calcd. for

C₁₆H₂₀O₃Na [M + Na]⁺283.1310; found 283.1297.

(E)-Ethyl 4-Oxo-8-(4-tolyl)oct-7-enoate (2c): According to general

procedure B, the reaction of 2aЈ (1.8 g, 10 mmol), 4-methylstyrene

(5 mL, 40 mmol), and Grubbs’ 2^ndgeneration catalyst (212 mg,

0.3 mmol) in dry CH₂Cl₂(50 mL) gave 2c (1.7 g, 64% yield) as a

pale yellow viscous oil after purification by column chromatog-

raphy (SiO₂, 100% hexanes to 10% EtOAc in hexanes). FTIR

hexanes)]. Compound 3a: FTIR (CHCl ): ν = 1787, 1643, 1475,

˜

3

1

1441, 1214, 1211, 1151, 1063, 971, 920 cm^–1. H NMR (500 MHz,

CDCl₃): δ = 7.54 (d, J = 7.3 Hz, 2 H, 2ϫ ArH), 7.43–7.35 (m, 1

H, ArH), 7.35–7.25 (m, 2 H, 2ϫ ArH), 5.75 (ddt, J = 16.5, 10.3,

6.1 Hz, 1 H, CH=CH₂), 5.02 (dd, J = 16.1, 1.1 Hz, 1 H,

CH=CHH), 4.96 (d, J = 10.2 Hz, 1 H, CH=CHH), 2.70–2.60 (m,

1 H, CHH), 2.55–2.45 (m, 2 H, CH₂), 2.25–2.05 (m, 4 H, 2ϫ CH₂),

1.95–1.80 (m, 1 H, CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

175.3 (C), 136.8 (2ϫ CH), 136.6 (CH), 130.1 (t, J = 287.0 Hz,

CF₂), 130.1 (CH), 129.1 (2ϫ CH), 124.7 (C), 115.7 (CH₂), 88.0 (t,

J = 25.0 Hz, C), 33.8 (CH₂), 28.3 (CH₂), 26.8 (CH₂), 26.0 (CH₂)

ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –84.1 (d, J = 210.4 Hz, 1

F), –85.0 (d, J = 210.4 Hz, 1 F) ppm. MS: m/z (%) = 299 (100) [M

+ H]⁺, 279 (31), 251 (54), 241 (11), 231 (8), 169 (9), 149 (17), 147

(26), 121 (18), 111 (20), 93 (6), 83 (3), 55 (13). HRMS (ESI-TOF):

calcd. for C₁₅H₁₆F₂O₂Na [M + Na]⁺321.0737; found 321.0757.

(CHCl ): ν = 1720, 1514, 1445, 1412, 1376, 1192, 1034, 969 cm^–1.

˜

3

¹H NMR (500 MHz, CDCl₃): δ = 7.22 (d, J = 8.1 Hz, 2 H, 2ϫ

ArH), 7.09 (d, J = 8.1 Hz, 2 H, 2ϫ ArH), 6.37 (d, J = 15.8 Hz, 1

H, CH=CH), 6.13 (dt, J = 15.8, 6.8 Hz, 1 H, CH=CH), 4.13 (q, J

= 7.1 Hz, 2 H, OCH₂), 2.74 (t, J = 6.4 Hz, 2 H, CH₂), 2.63 (t, J =

7.2 Hz, 2 H, CH₂), 2.59 (t, J = 6.3 Hz, 2 H, CH₂), 2.53–2.41 (m, 2

H, CH₂), 2.32 (s, 3 H, CH₃), 1.25 (t, J = 7.2 Hz, 3 H, CH₃) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 208.0 (C), 172.7 (C), 136.8 (C),

134.6 (C), 130.6 (CH), 129.1 (2ϫ CH), 127.7 (CH), 125.9 (2ϫ CH),

60.6 (CH₂), 42.3 (CH₂), 37.1 (CH₂), 28.0 (CH₂), 27.0 (CH₂), 21.1

(CH₃), 14.1 (CH₃) ppm. MS: m/z (%) = 275 (8) [M + H]⁺, 247 (48),

257 (14), 256 (66), 229 (19), 228 (40), 169 (75), 168 (30), 131 (100),

129 (95), 128 (51), 115 (47), 91 (50), 77 (14), 55 (21). HRMS (ESI-

Compound 6: FTIR (CHCl ): ν = 3570, 1642, 1475, 1441, 1214,

˜

3

1

1067, 1033, 971, 918 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.70

(d, J = 7.0 Hz, 2 H, 2ϫ ArH), 7.65 (d, J = 7.1 Hz, 2 H, 2ϫ ArH),

7.55–7.30 (m, 6 H, 6ϫ ArH), 5.91 (ddt, J = 16.8, 12.9, 6.5 Hz, 1

H, CH=CH₂), 5.14 (dd, J = 17.2, 1.6 Hz, 1 H, CH=CHH), 5.06

(d, J = 10.2, 1.6 Hz, 1 H, CH=CHH), 3.28 (s, 1 H, OH), 2.66–2.54

(m, 1 H, CHH), 2.49 (dd, J = 13.3, 9.6 Hz, 1 H, CHH), 2.40–2.24

(m, 3 H, 3ϫ CHH), 2.22–2.10 (m, 2 H, 2ϫ CHH), 2.06–2.15 (m,

1 H, CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 138.0 (CH),

136.9 (2ϫ CH), 136.7 (2ϫ CH), 131.0 (dd, J = 288.5, 284.4 Hz,

CF₂), 129.9 (CH), 129.7 (CH), 129.0 (2ϫ CH), 128.9 (2ϫ CH),

126.3 (d, J = 285.6 Hz, CF₂), 125.9 (C), 115.0 (CH₂), 125.7 (C),

107.0 (t, J = 28.0 Hz, C), 91.5 (dd, J = 24.0, 21.0 Hz, C), 35.7

(CH₂), 33.5 (CH₂), 29.9 (CH₂), 27.9 (CH₂) ppm. ¹⁹F NMR

(470 MHz, CDCl₃): δ = –80.9 (d, J = 210.8 Hz, 1 F), –83.3 (d, J =

210.8 Hz, 1 F), –85.9 (s, 2 F) ppm. MS: m/z (%) = 458 (7) [M]⁺,

440 (47) [M – H₂O]⁺, 331 (74), 279 (68), 271 (31), 251 (28), 231

(40), 189 (47), 159 (36), 147 (100), 135 (71), 109 (54), 77 (52).

HRMS (ESI-TOF): calcd. for C₂₂H₂₂F₄O₂S₂Na [M + Na]⁺

481.0895; found 481.0896.

TOF): calcd. for C₁₇H₂₂O₃Na [M

297.1462.

+

Na]⁺297.1467; found

(E)-Ethyl 8-(Naphthalen-2-yl)-4-oxooct-7-enoate (2d): According to

general procedure B, the reaction of 2aЈ (1.4 g, 8 mmol), 2-vinyl-

naphthalene (3.6 g, 23 mmol), and Grubbs’ 2^ndgeneration catalyst

(141 mg, 0.2 mmol) in dry CH₂Cl₂(50 mL) gave 2d (1.3 g, 55%) as

a pale yellow viscous oil after purification by column chromatog-

raphy (SiO₂, 100% hexanes to 10% EtOAc in hexanes). FTIR

(CHCl ): ν = 1718, 1410, 1375, 1187, 1098, 1019, 966 cm^–1. ¹H

˜

3

NMR (300 MHz, CDCl₃): δ = 7.74–7.62 (m, 3 H, 3ϫ ArH), 7.58

(s, 1 H, ArH), 7.46 (dd, J = 8.6, 1.7 Hz, 1 H, ArH), 7.42–7.26 (m,

2 H, 2ϫ ArH), 6.48 (d, J = 15.8 Hz, 1 H, CH=CH), 6.23 (dt, J =

15.8, 6.7 Hz, 1 H, CH=CH), 4.05 (q, J = 7.1 Hz, 2 H, OCH₂),

2.75–2.35 (m, 8 H, 4ϫ CH₂), 1.16 (t, J = 7.1 Hz, 3 H, CH₃) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 208.1 (C), 172.7 (C), 134.8 (C),

133.6 (C), 132.7 (C), 130.8 (CH), 129.1 (CH), 128.0 (CH), 127.8

(CH), 127.6 (CH), 126.1 (CH), 125.3 (CH), 125.5 (CH), 123.4

(CH), 60.6 (CH₂), 42.2 (CH₂), 37.1 (CH₂), 28.0 (CH₂), 27.1 (CH₂),

14.1 (CH₃) ppm. MS: m/z (%) = 311 (9) [M + H]⁺, 310 (27) [M]⁺, Preparation of 3a from 2aЈ: According to general procedure C, a

292 (100), 264 (14), 218 (11), 204 (23), 191 (10), 179 (59), 165 (65), solution of 1 (143 mg, 0.6 mmol) and 2aЈ (97 mg, 0.5 mmol) in dry

6

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Synthesis of gem-Difluoromethylenated Spiro-γ-butyrolactones

THF (1 mL) was treated with 10 mol-% TBAF solution (0.25 mL,

0.1 mmol, 0.24 m solution in dry THF) at –78 °C, followed by treat-

(CH), 130.2 (t, J = 287.5 Hz, CF₂), 129.1 (2ϫ CH), 128.7 (CH),

128.2 (CH), 127.9 (CH), 127.6 (CH), 126.2 (CH), 125.7 (2ϫ CH),

ment with a catalytic amount of pTsOH in CH₂Cl₂(2 mL) to give 124.7 (C), 123.4 (CH), 88.0 (t, J = 24.9 Hz, C), 34.4 (CH₂), 28.4

3a (145 mg, 97% yield) as a white solid.

(CH₂), 26.4 (CH₂), 26.2 (CH₂) ppm. ¹⁹F NMR (470 MHz, CDCl₃):

δ = –84.2 (d, J = 210.8 Hz, 1 F), –84.9 (d, J = 210.8 Hz, 1 F) ppm.

MS: m/z (%) = 425 (2) [M + H]⁺, 424 (3) [M]⁺, 310 (23), 293 (26),

292 (100), 265 (4), 205 (16), 191 (15), 179 (55), 165 (56), 152 (26),

141 (31), 129 (15), 101 (10), 73 (5), 55 (6). HRMS (ESI-TOF):

calcd. for C₂₅H₂₂F₂O₂SNa [M + Na]⁺447.1206; found 447.1208.

γ-[Difluoro(phenylsulfanyl)methyl]-γ-(4-phenylbutyl-3-ene)-γ-butyro-

lactone (3b): According to general procedure C, the reaction of 1

(289 mg, 1.2 mmol) and 2b (262 mg, 1 mmol) and purification by

column chromatography (SiO₂, 8% EtOAc and 2% CH₂Cl₂in hex-

anes) provided 3b (350 mg, 94% yield) as a white solid [m.p. 68–

69 °C (hexanes)]. FTIR (CHCl ): ν = 1787, 1497, 1475, 1463, 1442,

γ-[Difluoro(phenylsulfanyl)methyl]-γ-hydroxyisobenzo-furan-1(3H)-

one (4): According to the literature procedure,^[3a]a mixture of 1

(1.4 g, 6 mmol) and phthalic anhydride (0.4 g, 3 mmol) in dry THF

(8 mL) was treated with 10 mol-% TBAT (0.4 g, 0.7 mmol) at

–20 °C. The reaction mixture was stirred at –20 °C and slowly

˜

3

1214, 1215, 1173, 1063, 969 cm^–1. H NMR (500 MHz, CDCl₃): δ

1

= 7.54 (d, J = 7.26 Hz, 2 H, 2ϫ ArH), 7.40–7.34 (m, 1 H, ArH),

7.31–7.18 (m, 6 H, 6ϫ ArH), 7.17–7.09 (m, 1 H, ArH), 6.37 (d, J

= 15.9 Hz, 1 H, CH=CH), 6.10 (dt, J = 15.8, 6.6 Hz, 1 H,

CH=CH), 2.73–2.58 (m, 1 H, CHH), 2.57–2.43 (m, 2 H, CH₂), warmed to room temperature overnight. The reaction was

2.33–2.05 (m, 4 H, 2ϫ CH₂), 2.00–1.80 (m, 1 H, CHH) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 175.3 (C), 137.1 (C), 136.8 (2ϫ CH),

131.2 (CH), 130.1 (t, J = 281.6 Hz, CF₂), 130.1 (CH), 129.1 (2ϫ

CH), 128.5 (2ϫ CH), 128.2 (CH), 127.2 (CH), 126.0 (2ϫ CH),

124.7 (C), 87.9 (t, J = 24.9 Hz, C), 34.3 (CH₂), 28.3 (CH₂), 26.2

quenched with H₂O (3 mL) and extracted with EtOAc (3ϫ 25 mL).

The organic phase was washed successively with water and brine

and dried with anhydrous Na₂SO₄. After solvent removal, a crude

product was purified by column chromatography (SiO₂, 20 %

EtOAc in hexanes) to give 4 (0.85 g, 88% yield) as white needles

(CH₂), 26.1 (CH₂) ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –84.2 [m.p. 79–80 °C (CH Cl /hexanes)]. FTIR (CHCl ): ν = 3120, 1757,

˜

2

3

(d, J = 210.9 Hz, 1 F), –84.9 (d, J = 210.9 Hz, 1 F) ppm. MS: m/z

1468, 1441, 1063, 1044, 764, 747 cm^–1

.

¹H NMR (500 MHz,

(%) = 375 (100) [M + H]⁺, 335 (22), 311 (3), 225 (18), 177 (13), CDCl₃): δ = 7.95 (d, J = 8.3 Hz, 1 H, ArH), 7.80–7.74 (m, 2 H,

179 (20), 165 (10), 117 (7), 91 (4). HRMS (ESI-TOF): calcd. for 2ϫ ArH), 7.73–7.68 (m, 1 H, ArH), 7.60 (d, J = 7.4 Hz, 2 H, 2ϫ

C₂₁H₂₀F₂O₂SNa [M + Na]⁺397.1050; found 397.1072.

ArH), 7.50–7.44 (m, 1 H, ArH), 7.43–7.36 (m, 2 H, 2ϫ ArH), 4.69

(br, 1 H, OH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 166.8 (C),

143.0 (2ϫ C), 136.8 (2ϫ CH), 134.9 (CH), 131.9 (CH), 130.3 (CH),

129.2 (2 ϫ CH), 127.4 (C), 126.4 (t, J = 287.3 Hz, CF₂), 124.5

(CH), 124.0 (CH), 102.9 (t, J = 30.4 Hz, C) ppm. ¹⁹F NMR

(470 MHz, CDCl₃): δ = –84.5 (d, J = 213.4 Hz, 1 F), –87.1 (d, J =

213.4 Hz, 1 F) ppm. MS: m/z (%) = 309 (12) [M + H]⁺, 308 (8)

[M]⁺, 160 (38), 149 (100), 121 (22), 110 (10), 93 (10), 77 (5), 65

(17), 51 (5). HRMS (ESI-TOF): calcd. for C₁₅H₁₀F₂O₃SNa [M +

Na]⁺331.0216; found 331.0231.

γ-[Difluoro(phenylsulfanyl)methyl]-γ-(4-tolylbutyl-3-ene)-γ-butyro-

lactone (3c): According to general procedure C, the reaction of 1

(297 mg, 1.2 mmol) and 2c (295 mg, 1 mmol) and purification by

column chromatography (SiO₂, 8% EtOAc and 2% CH₂Cl₂in hex-

anes) provided 3c (376 mg, 93% yield) as a white solid [m.p. 89–

90 °C (hexanes)]. FTIR (CHCl ): ν = 1787, 1513, 1475, 1442, 1235,

˜

3

1172, 1150, 1060, 970 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.55

(d, J = 7.2 Hz, 2 H, 2ϫ ArH), 7.38 (dd, J = 7.4, 7.4 Hz, 1 H,

ArH), 7.32 (dd, J = 7.7, 7.7 Hz, 2 H, 2ϫ ArH), 7.17 (d, J = 7.6 Hz,

2 H, 2ϫ ArH), 7.04 (d, J = 8.0 Hz, 2 H, 2ϫ ArH), 6.35 (d, J =

15.9 Hz, 1 H, CH=CH), 6.06 (dt, J = 15.7, 6.6 Hz, 1 H, CH=CH),

2.73–2.58 (m, 1 H, CHH), 2.57–2.43 (m, 2 H, 2ϫ CHH), 2.33–2.05

(m, 7 H, CH₃, 2ϫ CH₂), 2.00–1.80 (m, 1 H, CHH) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 175.4 (C), 137.1 (C), 136.9 (2ϫ CH), 134.4

(C), 131.1 (CH), 130.2 (t, J = 288.5 Hz, CF₂), 130.2 (CH), 129.2

(2ϫ CH), 129.1 (2ϫ CH), 127.1 (CH), 125.9 (2ϫ CH), 124.7 (C),

88.0 (t, J = 25.1 Hz, C), 34.4 (CH₂), 28.4 (CH₂), 26.3 (CH₂), 26.1

(CH₂), 21.1 (CH₃) ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –84.3

(d, J = 210.4 Hz, 1 F), –85.0 (d, J = 210.4 Hz, 1 F) ppm. MS: m/z

(%) = 389 (18) [M + H]⁺, 388 (76) [M]⁺, 280 (8), 279 (39), 259 (25),

241 (33), 239 (42), 231 (16), 213 (36), 199 (29), 131 (62), 91 (39).

HRMS (ESI-TOF): calcd. for C₂₂H₂₂F₂O₂SNa [M + Na]⁺

411.1206; found 411.1216.

General Procedure D for the Preparation of γ-[Difluoro(phenylsulf-

anyl)methyl]-γ-butyrolactones 3e and 8a

3-(But-3-enyl)-3-[difluoro(phenylsulfanyl)methyl]isobenzofuran-

1(3H)-one (3e): A solution of homoallyl bromide (5 mL, 50 mmol)

in dry THF (40 mL) was slowly added by cannula over a period of

1 h to a suspension of magnesium turnings (1.9 g, 80 mmol) in dry

THF (40 mL). The reaction mixture was stirred at room tempera-

ture for 2 h. The resulting homoallylmagnesium bromide was

added dropwise over 45 min to a suspension of 4 (3.1 g, 10 mmol)

and tetra-n-butylammonium bromide (16.1 g, 50 mmol) in dry

THF (20 mL) at –78 °C. The reaction mixture was stirred at –78 °C

for 3 h. After the reaction was completed, it was quenched with

HCl (2 m, 20 mL) at –78 °C and extracted with EtOAc (4ϫ 50 mL).

The organic phase was washed with brine (50 mL) and dried with

anhydrous Na₂SO₄. After removal of the solvent, the crude product

was treated with a catalytic amount of pTsOH in dry CH₂Cl₂

(20 mL) under reflux overnight. After the solvent was removed, the

residue was diluted with water (20 mL) and extracted with EtOAc

(4ϫ 20 mL). The combined organic phase was washed with water

γ-[Difluoro(phenylsulfanyl)methyl]-γ-[4-(2-naphthyl)butyl-3-ene]-γ-

butyrolactone (3d): According to general procedure C, the reaction

of 1 (336.2 mg, 1.2 mmol) and 2c (312 mg, 1 mmol) and purifica-

tion by column chromatography (SiO₂, 8% EtOAc and 2% CH₂Cl₂

in hexanes) afforded 3d (403 mg, 94% yield) as a white solid [m.p.

97–98 °C (hexanes)]. FTIR (CHCl ): ν = 1787, 1508, 1475, 1441, (20 mL) and brine (20 mL) and dried with anhydrous Na₂SO₄. The

˜

3

1174, 1152, 1061, 970 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.50 crude product was purified by column chromatography (SiO₂, 10%

(t, J = 7.6 Hz, 3 H, 3ϫ ArH), 7.60 (s, 1 H, ArH), 7.55 (d, J =

7.1 Hz, 2 H, 2ϫ ArH), 7.49 (dd, J = 10.2, 1.7 Hz, 1 H, ArH), 7.43–

7.25 (m, 5 H, 5ϫ ArH), 6.53 (d, J = 15.9 Hz, 1 H, CH=CH), 6.23

EtOAc in hexanes) to afford 3e (2.2 g, 62% yield) as a pale yellow

viscous oil and 7 (642 mg, 23% yield) as a white solid [m.p. 75–

76 °C (CH Cl /hexanes)]. Compound 3e: FTIR (CHCl ): ν = 1783,

˜

2

3

(dt, J = 15.7, 6.5 Hz, 1 H, CH=CH), 2.73–2.58 (m, 1 H, CHH), 1644, 1467, 1287, 920 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.87

2.57–2.43 (m, 2 H, CH₂), 2.33–2.05 (m, 4 H, 2ϫ CH₂), 2.00–1.80 (d, J = 7.6 Hz, 1 H, ArH), 7.63 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H,

(m, 1 H, CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 175.4 (C),

136.9 (2ϫ CH), 134.6 (C), 133.6 (C), 132.8 (C), 131.3 (CH), 130.2

ArH), 7.55 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H, ArH), 7.48 (d, J =

7.7 Hz, 1 H, ArH), 7.42 (d, J = 7.1 Hz, 2 H, 2ϫ ArH), 7.36–7.29

Eur. J. Org. Chem. 0000, 0–0

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M. Pohmakotr et al.

FULL PAPER

(m, 1 H, ArH), 7.28–7.21 (m, 2 H, 2ϫ ArH), 5.59 (ddt, J = 16.4, night. After completion of the reaction, the solvent was evaporated,

13.1, 6.5 Hz, 1 H, CH=CH₂), 4.88–4.75 (m, 2 H, CH=CH₂), 2.49 and the crude product was purified by column chromatography

(ddd, J = 14.5, 11.3, 5.1 Hz, 1 H, CHH), 2.25 (ddd, J = 14.6, 11.3,

5.0 Hz, 1 H, CHH), 1.92–1.80 (m, 1 H, CHH), 1.52–1.39 (m, 1 H,

CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 168.7 (C), 145.7

(C), 136.7 (2ϫ CH), 136.3 (CH), 134.4 (CH), 130.5 (CH), 130.0

(CH), 129.0 (2ϫ CH), 128.3 (t, J = 287.6 Hz, CF₂), 127.4 (C),

(SiO₂, 100% hexanes to 10% EtOAc in hexanes) to give 3f (E/Z =

13:1; 814 mg, 64% yield) as a colorless viscous oil. FTIR (CHCl₃):

ν = 1789, 1600, 1467, 1287, 966 cm^–1. ¹H NMR (500 MHz, CDCl ,

˜

3

major isomer marked *): δ = 7.84 (ddd, J = 7.6, 0.7, 0.7 Hz, 1 H,

ArH*), 7.80 (ddd, J = 7.7, 0.8, 0.8 Hz, 1 H, ArH minor), 7.64–7.55

125.8 (CH), 125.1 (C), 123.4 (CH), 115.6 (CH₂), 89.2 (t, J = (m, 2 H, 2ϫ ArH major and minor), 7.53–7.45 (m, 4 H, 4ϫ ArH

27.8 Hz, C), 31.2 (CH₂), 26.7 (CH₂) ppm. ¹⁹F NMR (470 MHz,

CDCl₃): δ = –80.8 (d, J = 212.7 Hz, 1 F), –82.3 (d, J = 212.7 Hz,

1 F) ppm. MS: m/z (%) = 347 (100) [M + H]⁺, 346 (9), 327 (4), 261

(3), 237 (9), 217 (21), 197 (17), 187 (42), 169 (100), 151 (8), 141

(30), 129 (8), 77 (7), 65 (6). HRMS (ESI-TOF): calcd. for

major and minor), 7.38–7.33 (m, 4 H, 4ϫ ArH major and minor),

7.33–7.26 (m, 2 H, 2ϫ ArH major and minor), 7.26–7.19 (m, 4 H,

4ϫ ArH major and minor), 7.19–7.12 (m, 8 H, 8ϫ ArH major and

minor), 7.11–7.05 (m, 1 H, ArH*), 7.04–6.93 (m, 1 H, ArH minor),

6.28 (d, J = 15.8 Hz, 1 H, CH=CH minor), 6.11 (d, J = 15.8 Hz, 1

H, CH=CH*), 5.89 (dt, J = 15.8, 6.9 Hz, 1 H, CH=CH*), 5.57 (dt,

J = 15.3, 7.4 Hz, 1 H, CH=CH minor), 3.21 (dd, J = 14.8, 7.2 Hz,

1 H, CHH minor), 3.06 (dd, J = 14.5, 7.3 Hz, 1 H, CHH minor),

2.65–2.45 (m, 1 H, CHH*), 2.40–2.25 (m, 1 H, CHH*), 2.10–1.95

(m, 2 H, 2ϫ CHH major and minor), 1.70–1.55 (m, 2 H, 2ϫ CHH

major and minor) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 168.6

C₁₉H₁₆F₂O₂SNa [M + Na]⁺369.0737; found 369.0734. Compound

1

7: FTIR (CHCl ): ν = 1784, 1602, 1475, 1286, 976 cm^–1. H NMR

˜

3

(500 MHz, CDCl₃): δ = 7.98 (d, J = 8.5 Hz, 1 H, ArH), 7.73 (ddd,

J = 8.4, 8.4, 1.1 Hz, 1 H, ArH), 7.66 (d, J = 7.5 Hz, 2 H, 2ϫ ArH),

7.60 (d, J = 7.1 Hz, 2 H, 2ϫ ArH), 7.50–7.43 (m, J = 6.5, 1.3 Hz,

1 H, ArH), 7.42–7.34 (m, 2 H, 2ϫ ArH), 5.65 (dd, J = 10.5, 5.3 Hz,

1 H, CF₂CH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 168.8 (C), (C), 145.6 (C), 137.1 (C), 136.7 (2ϫ CH), 134.5 (CH), 131.0 (CH),

142.3 (C), 136.7 (2ϫ CH), 134.5 (CH), 130.6 (CH), 130.3 (CH),

130.5 (CH), 130.0 (CH), 129.0 (2ϫ CH), 128.4 (2ϫ CH), 128.3 (t,

129.2 (2 ϫ CH), 126.5 (t, J = 282.0 Hz, CF₂), 126.5 (C), 125.9 J = 288.0 Hz, CF₂), 127.9 (CH), 127.3 (C), 127.1 (CH), 125.9 (2ϫ

(CH), 124.9 (C), 124.1 (CH), 79.6 (t, J = 32.4 Hz, CH) ppm. ¹⁹F

NMR (376 MHz, CDCl₃): δ = –79.0 (d, J = 216.5 Hz, 1 F), –85.5

(dd, J = 216.5, 10.6 Hz, 1 F) ppm. MS: m/z (%) = 293 (28) [M +

H]⁺, 292 (59) [M]⁺, 160 (14), 159 (100), 133 (70), 127 (12), 105 (17),

99 (1), 77 (30). HRMS (ESI-TOF): calcd. for C₁₅H₁₀F₂O₂SNa [M

+ Na]⁺315.0267; found 315.0261.

CH), 125.8 (CH), 125.0 (C), 123.4 (CH), 89.2 (t, J = 27.6 Hz, C),

31.5 (CH₂), 26.1 (CH₂) ppm. Owing to low signal intensity, the

minor isomer could not be detected by ¹³C NMR spectroscopy. ¹⁹

F

NMR (376 MHz, CDCl₃): δ = –67.1 (d, J = 225.6 Hz, 1 F minor),

–67.5 (d, J = 212.5 Hz, 1 F*), –68.5. (d, J = 225.6 Hz, 1 F minor),

–68.8 (d, J = 212.8 Hz, 1 F*) ppm. MS: m/z (%) = 423 (51) [M +

H]⁺, 422 (35) [M]⁺, 333 (12), 332 (35), 313 (20), 276 (13), 273 (16),

223 (22), 203 (51), 183 (16), 175 (59), 159 (35), 149 (25), 131 (22),

117 (62), 115 (100), 105 (31), 91 (55), 77 (54), 65 (22). HRMS (ESI-

TOF): calcd. for C₂₅H₂₀F₂O₂SNa [M + Na]⁺445.1050; found

445.1059.

3-[Difluoro(phenylsulfanyl)methyl]-3-(pent-4-enyl)isobenzofuran-

1(3H)-one (8a): According to general procedure D, a solution of

the Grignard reagent generated from magnesium turnings (2.0 g,

80 mmol) and 5-bromopent-1-ene (6 mL, 50 mmol) in dry THF

(80 mL) was treated with 4 (3 g, 10 mmol) and tetra-n-butylammo-

nium bromide (16 g, 50 mmol) in dry THF (20 mL) to give 8a (2 g,

58% yield) as a pale yellow viscous oil and 7 (0.85 g, 29% yield)

as a white solid after purification by column chromatography

E/Z Mixture of 3-[Difluoro(phenylsulfanyl)methyl]-3-(4-tolylbut-3-

enyl)isobenzofuran-1(3H)-one (3g): According to general procedure

E, the reaction of 3e (1 g, 3 mmol), 4-methylstyrene (1.6 mL,

12 mmol), and Grubbs’ 2^ndgeneration catalyst (64 mg, 75 μmol) in

dry CH₂Cl₂(20 mL) gave 3g (E/Z = 16:1; 872 mg, 63% yield) as a

colorless viscous oil after purification by column chromatography

(SiO , 10% EtOAc in hexanes). Compound 8a: FTIR (CHCl ): ν

˜

2

3

1

= 1783, 1644, 1467, 1287, 920 cm^–1. H NMR (500 MHz, CDCl₃):

δ = 7.94 (d, J = 7.6 Hz, 1 H, ArH), 7.69 (ddd, J = 7.5, 7.5, 1.1 Hz,

1 H, ArH), 7.69 (ddd, J = 7.6, 7.6, 0.8 Hz, 1 H, ArH), 7.54 (d, J

= 7.7 Hz, 1 H, ArH), 7.49 (d, J = 7.1 Hz, 2 H, 2ϫ ArH), 7.45–

7.34 (m, 1 H, ArH), 7.31 (t, J = 7.7 Hz, 2 H, 2ϫ ArH), 5.64 (ddt,

J = 17.0, 13.4, 6.7 Hz, 1 H, CH=CH₂), 5.00–4.85 (m, 2 H,

CH=CH₂), 2.50–2.35 (m, 1 H, CHH), 2.30–2.18 (m, 1 H, CHH),

2.10–1.90 (m, 2 H, CH₂), 1.38–1.20 (m, 1 H, CHH), 0.90–0.70 (m,

1 H, CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 168.8 (C),

145.9 (C), 137.3 (CH), 136.7 (2ϫ CH), 134.4 (CH), 130.4 (CH),

130.0 (CH), 128.9 (2ϫ CH), 128.3 (t, J = 286.3 Hz, CF₂), 127.2

(C), 125.8 (CH), 125.1 (CH), 123.3 (C), 115.4 (CH₂), 89.4 (t, J =

27.4 Hz, C), 33.1 (CH₂), 31.3 (CH₂), 21.5 (CH₂) ppm. ¹⁹F NMR

(376 MHz, CDCl₃): δ = –80.8 (d, J = 212.7 Hz, 1 F), –82.3 (d, J =

212.7 Hz, 1 F) ppm. MS: m/z (%) = 361 (28) [M + H]⁺, 360 (8)

[M]⁺, 251 (19), 211 (14), 201 (30), 183 (70), 165 (100), 159 (22), 155

(17), 147 (12), 131 (11), 103 (14), 91 (3), 77 (9), 76 (3). HRMS

(ESI-TOF): calcd. for C₂₀H₁₈F₂O₂SNa [M + Na]⁺383.0893; found

383.0896.

(SiO₂, 100% hexanes to 10% EtOAc in hexanes). FTIR (CHCl₃):

1

ν = 1789, 1600, 1513, 1467, 1287, 968 cm^–1. H NMR (500 MHz,

˜

CDCl₃, major isomer marked *): δ = 8.19 (d, J = 7.6 Hz, 1 H,

ArH*), 8.14 (d, J = 7.6 Hz, 1 H, ArH minor), 8.00–7.90 (m, 2 H,

2ϫ ArH major and minor), 7.83–7.79 (m, 4 H, 4ϫ ArH major and

minor), 7.78–7.70 (m, 4 H, 4ϫ ArH major and minor), 7.70–7.60

(m, 2 H, 2ϫ ArH major and minor), 7.60–7.53 (m, 4 H, 4ϫ ArH

major and minor), 7.43–7.30 (m, 4 H, 4ϫ ArH major and minor),

7.30–7.27 (m, 4 H, 4ϫ ArH major and minor), 6.59 (d, J = 15.8 Hz,

1 H, CH=CH minor), 6.43 (d, J = 15.8 Hz, 1 H, CH=CH*), 6.19

(dt, J = 15.7, 6.9 Hz, 1 H, CH=CH*), 5.86 (dt, J = 15.7, 7.8 Hz, 1

H, CH=CH minor), 3.55 (dd, J = 14.6, 7.3 Hz, 1 H, CHH minor),

3.39 (dd, J = 14.4, 7.4 Hz, 1 H, CHH minor), 3.00–2.80 (m, 1 H,

CHH*), 2.73–2.60 (m, 1 H, CHH*), 2.56 (s, 3 H, CH₃*), 2.52 (s, 3

H, CH₃minor), 2.43–2.30 (m, 2 H, CHH major and minor), 2.10–

1.83 (m, 2 H, CHH major and minor) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 168.6 (C), 145.7 (C), 136.9 (C), 136.7 (2ϫ CH), 134.4

(CH), 134.3 (C), 130.8 (CH), 130.5 (CH), 130.0 (CH), 129.1 (2ϫ

CH), 129.0 (2ϫ CH), 128.8 (t, J = 276.1 Hz, CF₂), 127.3 (C), 126.8

(CH), 125.8 (3ϫ CH), 125.8 (C), 123.4 (CH), 89.1 (t, J = 27.6 Hz,

C), 31.6 (CH₂), 26.0 (CH₂), 21.1 (CH₃) ppm. Owing to low signal

intensity, the minor isomer could not be detected by ¹³C NMR

General Procedure E for the Preparation of γ-[Difluoro(phenylsulf-

anyl)methyl]-γ-butyrolactones 3f–3h and 8b–8e

E/Z Mixture of 3-[Difluoro(phenylsulfanyl)methyl]-3-(4-phenylbut-3-

enyl)isobenzofuran-1(3H)-one (3f): A solution of 3e (1 g, 3 mmol),

styrene (1.4 mL, 12 mmol), and Grubbs’ 2^ndgeneration catalyst spectroscopy. ¹⁹F NMR (376 MHz, CDCl₃): δ = –80.5 (d, J =

(64 mg, 75 μmol) in dry CH₂Cl₂(20 mL) was heated at reflux over-

214.5 Hz, 1 F minor), –80.9 (d, J = 214.5 Hz, 1 F*), –81.8 (d, J =

8

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Synthesis of gem-Difluoromethylenated Spiro-γ-butyrolactones

214.5 Hz, 1 F minor), –82.3 (d, J = 214.5 Hz, 1 F*) ppm. MS: m/z

= 16.5, 12.2, 4.4 Hz, 1 H, CHH*), 2.33 (ddd, J = 15.9, 10.9, 5.3 Hz,

(%) = 437 (28) [M + H]⁺, 436 (43) [M]⁺, 347 (43), 327 (61), 323 1 H, CHH minor), 2.21 (ddd, J = 13.3, 13.3, 4.6 Hz, 1 H, CHH*),

(93), 289 (48), 279 (55), 259 (30), 251 (57), 235 (18), 159 (39), 131

2.16–2.00 (m, 4 H, 4ϫ CHH major and minor), 1.50–1.04 (m, 1 H,

(80), 129 (77), 115 (58), 105 (69), 91 (100), 77 (72), 65 (24). HRMS CHH minor), 1.38–1.24 (m, 1 H, CHH*), 0.88–0.72 (m, 2 H, 2ϫ

(ESI-TOF): calcd. for C₂₆H₂₂F₂O₂SNa [M + Na]⁺459.1206; found

459.1206.

CHH major and minor) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

168.8 (C), 145.9 (C), 137.4 (C), 136.7 (2ϫ CH), 134.4 (CH), 130.9

(CH), 130.5 (CH), 130.0 (CH), 129.2 (CH), 129.0 (2ϫ CH) 128.5

(2ϫ CH), 128.3 (t, J = 230.3 Hz, CF₂), 127.3 (C), 127.0 (CH),

126.0 (2ϫ CH), 125.9 (CH), 125.1 (C), 123.3 (CH), 89.4 (t, J =

27.8 Hz, C), 32.5 (CH₂), 31.5 (CH₂), 26.1 (CH₂) ppm. Owing to

low signal intensity, the minor isomer could not be detected by ¹³C

NMR spectroscopy. ¹⁹F NMR (376 MHz, CDCl₃): δ = –80.9 (d, J

= 218.5 Hz, 1 F, CFF*), –81.0 (d, J = 218.5 Hz, 1 F, CFF minor),

–82.2 (d, J = 210.2 Hz, 1 F, CFF*), –82.3 (d, J = 218.8 Hz, 1 F,

CFF minor) ppm. MS: m/z (%) = 437 (9) [M + H]⁺, 436 (17)

[M]⁺, 327 (52), 307 (11), 287 (35), 259 (22), 133 (26), 130 (10), 129

(42), 115 (36), 91 (35), 77 (9) cm^–1. HRMS (ESI-TOF): calcd. for

C₂₆H₂₂F₂O₂SNa [M + Na]⁺459.1206; found 459.1202.

E/Z Mixture of 3-[Difluoro(phenylsulfanyl)methyl]-3-[4-(3-meth-

oxyphenyl)but-3-enyl]isobenzofuran-1(3H)-one (3h): According to

general procedure E, the reaction of 3e (1 g, 3 mmol), 3-meth-

oxystyrene (1.6 mL, 12 mmol), and Grubbs’ 2^ndgeneration catalyst

(64 mg, 75 μmol) in dry CH₂Cl₂(20 mL) gave 3h (E/Z = 13:1; 1 g,

73% yield) as a colorless viscous oil after purification by column

chromatography (SiO₂, 100% hexanes to 10% EtOAc in hexanes).

FTIR (neat): ν = 1789, 1600, 1580, 1470, 1288, 1156, 968 cm^–1. ¹H

˜

NMR (500 MHz, CDCl₃, major isomer marked *): δ = 7.84 (dd, J

= 7.6, 0.8 Hz, 1 H, ArH*), 7.79 (d, J = 7.6 Hz, 1 H, ArH minor),

7.63–7.54 (m, 2 H, 2ϫ ArH major and minor), 7.53–7.55 (m, 4 H,

4ϫ ArH major and minor), 7.43–7.33 (m, 4 H, 4ϫ ArH major and

minor), 7.32–7.26 (m, 2 H, 2ϫ ArH major and minor), 7.25–7.18 E/Z Mixture of 3-[Difluoro(phenylsulfanyl)methyl]-3-(4-tolylpent-4-

(m, 4 H, 4ϫ ArH major and minor), 7.08 (t, J = 7.9 Hz, 1 H, enyl)isobenzofuran-1(3H)-one (8c): According to general procedure

ArH*), 7.02 (t, J = 7.9 Hz, 1 H, ArH minor), 6.73 (d, J = 7.7 Hz,

1 H, ArH*), 6.70–6.58 (m, 4 H, 4ϫ ArH major and minor), 6.56–

E, the reaction of 8a (1 g, 2.6 mmol), 4-methylstyrene (1.6 mL,

12 mmol), and Grubbs’ 2^ndgeneration catalyst (64 mg, 75 μmol) in

6.45 (m, 1 H, ArH minor), 6.25 (d, J = 15.8 Hz, 1 H, CH=CH dry CH₂Cl₂(20 mL) gave 8c (E/Z = 5:1; 872 mg, 63% yield) as a

minor), 6.08 (d, J = 15.8 Hz, 1 H, CH=CH*), 6.19 (dt, J = 15.7, colorless viscous oil after purification by column chromatography

6.9 Hz, 1 H, CH=CH*), 5.56 (dt, J = 15.2, 7.4 Hz, 1 H, CH=CH (SiO , 100% hexanes to 10% EtOAc in hexanes). FTIR (neat): ν =

˜

2

minor), 3.68 (s, 3 H, OCH₃*), 3.63 (s, 3 H, CH₃minor), 3.20 (dd,

J = 14.6, 7.4 Hz, 1 H, CHH minor), 3.05 (dd, J = 14.5, 7.5 Hz, 1 CDCl₃, major isomer marked *): δ = 7.85 (ddd, J = 7.6, 1.0, 1.0 Hz,

H, CHH minor), 2.60–2.49 (m, 1 H, CHH*), 2.39–2.25 (m, 1 H, 1 H, ArH*), 7.68 (d, J = 8.1 Hz, 1 H, ArH minor), 7.63–7.55 (m,

1779, 1601, 1513, 1467, 1287, 969 cm^{–1 1}H NMR (500 MHz,

.

CHH*), 2.10–1.95 (m, 2 H, CHH major and minor), 1.70–1.55 (m, 2 H, 2ϫ ArH major and minor), 7.54–7.48 (m, 2 H, 2ϫ ArH major

2 H, CHH major and minor) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 168.6 (C), 159.7 (C), 145.6 (C), 138.5 (C), 136.6 (2ϫ CH),

and minor), 7.47–7.43 (m, 2 H, 2ϫ ArH major and minor), 7.43–

7.30 (m, 4 H, 4ϫ ArH major and minor), 7.34–7.23 (m, 2 H, 2ϫ

134.4 (CH), 130.9 (CH), 130.5 (CH), 130.0 (CH), 129.3 (CH), 128.9 ArH major and minor), 7.21–7.13 (m, 4 H, 4ϫ ArH major and

(2ϫ CH), 128.2 (t, J = 277.5 Hz, CF₂), 128.2 (CH), 127.3 (C),

125.8 (CH), 125.0 (C), 123.4 (CH), 118.6 (CH), 112.8 (CH), 111.3

minor), 7.13–7.06 (m, 2 H, 2ϫ ArH*), 7.05–7.02 (m, 2 H, 2ϫ ArH

minor), 7.02–6.95 (m, 4 H, 4ϫ ArH major and minor), 6.19 (d, J

(CH), 89.0 (t, J = 28.0 Hz, C), 55.1 (CH₃), 31.5 (CH₂), 26.0 (CH₂) = 15.8 Hz, 1 H, CH=CH*), 6.08 (d, J = 15.8 Hz, 1 H, CH=CH

ppm. Owing to low signal intensity, the minor isomer could not be

detected by ¹³C NMR spectroscopy. ¹⁹F NMR (376 MHz, CDCl₃):

δ = –80.5 (d, J = 209.8 Hz, 1 F minor), –80.9 (d, J = 213.2 Hz, 1

F*), –81.8 (d, J = 209.8 Hz, 1 F minor), –82.3 (d, J = 213.2 Hz, 1

F*) ppm. MS: m/z (%) = 452 (58) [M + H]⁺, 451 (64) [M]⁺, 343

(26), 323 (17), 305 (30), 303 (64), 275 (51), 215 (16), 161 (53), 147

minor), 5.98–5.80 (m, 2 H, 2 ϫ CH=CH*), 2.60–2.50 (m, 1 H,

CHH*), 2.45–2.32 (m, 2 H, 2ϫ CHH major and minor), 2.28–2.15

(m, 7 H, CHH*, 2ϫ CH₃major and minor), 2.14–1.98 (m, 2 H,

2ϫ CHH*), 1.98–1.85 (m, 2 H, 2ϫ CHH minor), 1.38–1.20 (m, 2

H, 2ϫ CHH major and minor), 0.88–0.70 (m, 2 H, 2ϫ CHH major

and minor) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 168.8 (C),

(100), 145 (47), 117 (15), 115 (34), 91 (86), 77 (19), 65 (9). HRMS 145.9 (C), 136.7 (C), 136.7 (2ϫ CH), 134.6 (C), 134.4 (CH), 130.7

(ESI-TOF): calcd. for C₂₆H₂₂F₂O₃SNa [M + Na]⁺475.1155; found

475.1151.

(CH), 130.4 (CH), 130.0 (CH), 129.1 (2ϫ CH), 128.9 (2ϫ CH),

128.3 (t, J = 287.8 Hz, CF₂), 128.1 (CH), 127.3 (C), 125.8 (3ϫ

CH), 125.1 (C), 123.3 (CH), 89.4 (t, J = 27.4 Hz, C), 32.4 (CH₂),

31.4 (CH₂), 22.2 (CH₂), 21.1 (CH₃) ppm. Owing to low signal in-

tensity, the minor isomer could not be detected by ¹³C NMR spec-

troscopy. ¹⁹F NMR (376 MHz, CDCl₃): δ = –80.8 (d, J = 212.0 Hz,

1 F*), –80.9 (d, J = 210.4 Hz, 1 F minor), –82.2 (d, J = 212.0 Hz,

1 F*), –82.3 (d, J = 210.4 Hz, 1 F minor) ppm. MS: m/z (%) = 451

(16) [M + H]⁺, 450 (33) [M]⁺, 341 (34), 301 (50), 145 (23), 144

(100), 131 (83), 129 (70), 115 (15), 105 (23), 91 (20), 77 (10). HRMS

(ESI-TOF): calcd. for C₂₇H₂₄F₂O₂SNa [M + Na]⁺473.1363; found

473.1357.

E/Z Mixture of 3-[Difluoro(phenylsulfanyl)methyl]-3-(5-phenylpent-

4-enyl)isobenzofuran-1(3H)-one (8b): According to general pro-

cedure E, the reaction of 8a (936 mg, 2.6 mmol), styrene (1.6 mL,

12 mmol), and Grubbs’ 2^ndgeneration catalyst (64 mg, 75 μmol) in

dry CH₂Cl₂(20 mL) gave 8b (E/Z = 4:1; 972 mg, 87% yield) a as

a colorless viscous oil after purification by column chromatography

(SiO₂, 100% hexanes to 10% EtOAc in hexanes). FTIR (CHCl₃):

ν = 1790, 1600, 1493, 1468, 1287, 1048, 967 cm^{–1 1}H NMR

.

˜

(500 MHz, CDCl₃, major isomer marked *): δ = 7.87 (ddd, J = 7.6,

0.9, 0.9 Hz, 1 H, ArH*), 7.82 (ddd, J = 7.5, 0.8, 0.8 Hz, 1 H, ArH

minor), 7.65–7.59 (m, 2 H, 2ϫ ArH major and minor), 7.58–7.49

(m, 2 H, 2ϫ ArH major and minor), 7.48–7.44 (m, 2 H, 2ϫ ArH

major and minor), 7.44–7.39 (m, 4 H, 4ϫ ArH major and minor),

7.35–7.29 (m, 2 H, 2ϫ ArH major and minor), 7.28–7.14 (m, 12 H,

E/Z Mixture of 3-[Difluoro(phenylsulfanyl)methyl]-3-[(3-meth-

oxyphenyl)pent-4-enyl]isobenzofuran-1(3H)-one (8d): According to

general procedure E, the reaction of 8a (936 g, 2.6 mmol), 3-meth-

oxystyrene (1.6 mL, 12 mmol), and Grubbs’ 2^ndgeneration catalyst

12ϫ ArH major and minor), 7.14–7.08 (m, 1 H, ArH*), 7.05–7.00 (64 mg, 75 μmol) in dry CH₂Cl₂(20 mL) gave 8d (E/Z = 5:1;

(m, 1 H, ArH minor), 6.24 (d, J = 15.8 Hz, 1 H, CH=CH*), 6.13

(d, J = 15.8 Hz, 1 H, CH=CH minor), 5.96 (dt, J = 15.8, 7.0 Hz,

1 H, CH=CH*), 5.92 (dt, J = 15.3, 6.9 Hz, 1 H, CH=CH minor),

2.58 (ddd, J = 15.7, 10.9, 5.1 Hz, 1 H, CHH minor), 2.41 (ddd, J

817 mg, 67% yield) as a colorless viscous oil after purification by

column chromatography (SiO₂, 100% hexanes to 10% EtOAc in

hexanes). FTIR (CHCl ): ν = 1790, 1500, 1580, 1468, 1288, 1265,

˜

3

1156, 968 cm^–1. ¹H NMR (400 MHz, CDCl₃, major isomer marked

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M. Pohmakotr et al.

FULL PAPER

*): δ = 8.00–7.86 (m, 2 H, 2ϫ ArH major and minor), 7.74–7.65

(m, 2 H, 2ϫ ArH major and minor), 7.65–7.44 (m, 8 H, 8ϫ ArH

major and minor), 7.44–7.36 (m, 2 H, 2ϫ ArH major and minor),

crude product, which was firstly purified by column chromatog-

raphy (SiO₂, hexanes and then CH₂Cl₂) to remove organotin by-

products. A colorless oil was obtained, which was then purified

7.36–7.27 (m, 4 H, 4ϫ ArH major and minor), 7.23–7.07 (m, 2 H, again by column chromatography (SiO₂, 15 % CH₂Cl₂and 2%

2ϫ ArH major and minor), 6.93–6.85 (m, 2 H, 2ϫ ArH major and

minor), 6.85–6.78 (m, 2 H, 2ϫ ArH major and minor), 6.78–6.60

(m, 2 H, 2ϫ ArH major and minor), 6.28 (d, J = 15.8 Hz, 1 H,

EtOAc in hexanes) to give 5aA (less polar; 135 mg, 35 % yield,

which contains 1 % of 5aB as determined by ¹H NMR spec-

troscopy) as a colorless liquid and 5aB (more polar; 127 mg, 33%

CH=CH*), 6.18 (d, J = 15.8 Hz, 1 H, CH=CH minor), 6.10–5.92 yield) as a colorless liquid. Compound 5aA: FTIR (CHCl ): ν =

˜

3

1

(m, 2 H, 2ϫ CH=CH major and minor), 3.79 (s, 3 H, OCH₃*),

3.74 (s, 3 H, OCH₃minor), 2.54–2.52 (m, 1 H, CHH minor), 2.51–

2.47 (m, 2 H, 2ϫ CHH major and minor), 2.47–2.00 (m, 5 H, 3ϫ

CHH*, 2ϫ CHH minor), 1.49–1.30 (m, 2 H, 2ϫ CHH major and

minor), 0.99–0.79 (m, 2 H, 2ϫ CHH major and minor) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 168.9 (C), 159.8 (C), 145.9 (C), 138.9

(C), 136.8 (2ϫ CH), 134.5 (CH), 130.8 (CH), 130.5 (CH), 130.1

(CH), 129.6 (CH), 129.5 (CH), 129.0 (2 ϫ CH), 128.3 (t, J =

287.0 Hz, CF₂), 127.3 (C), 125.9 (CH), 125.0 (C), 123.4 (CH), 118.7

1781, 1459, 1252, 1219, 1184, 1118, 1049, 1021, 993, 927 cm^–1. H

NMR (500 MHz, CDCl₃): δ = 2.73–2.58 (m, 1 H, CHHCO), 2.58–

2.35 (m, 3 H, CHHCO and 2ϫ CHH), 2.07–1.89 (m, 3 H, 3ϫ

CHH), 1.89–1.83 (m, 1 H, CHH), 1.37–1.25 (m, 1 H, CHH), 1.02

(d, J = 6.9 Hz, 3 H, CH₃) ppm. ¹³C NMR (125 MHz, CDCl₃): δ

= 175.7 (CO), 127.2 (dd, J = 264.5, 249.4 Hz, CF₂), 89.5 (dd, J =

32.4, 21.3 Hz, C), 36.0 (t, J = 21.4 Hz, CH), 32.2 (d, J = 4.0 Hz,

CH₂), 28.5 (CH₂), 25.6 (d, J = 9 Hz, CH₂), 24.8 (d, J = 3.1 Hz,

CH₂), 10.8 (d, J = 7.3 Hz, CH₃) ppm. ¹⁹F NMR (470 MHz,

(CH), 112.8 (CH), 111.3 (CH), 89.0 (t, J = 27.0 Hz, C), 55.2 CDCl₃): δ = –125.2 (dd, J = 230.3, 27.7 Hz, 1 F), –128.6 (dd, J =

(OCH₃), 32.5 (CH₂), 31.5 (CH₂), 21.1 (CH₂) ppm. Owing to low 230.3, 3.8 Hz, 1 F, CFF) ppm. MS: m/z (%) = 191 (8) [M + H]⁺,

signal intensity, the minor isomer could not be detected by ¹³C

NMR spectroscopy. ¹⁹F NMR (376 MHz, CDCl₃): δ = –80.8 (d, J

= 213.2 Hz, 1 F*), –80.9 (d, J = 210.9 Hz, 1 F minor), –82.2 (d, J

= 213.2 Hz, 1 F*), –82.3 (d, J = 210.9 Hz, 1 F minor) ppm. MS:

181 (55), 180 (33), 178 (13), 169 (7), 167 (21), 151 (14), 133 (14),

131 (39), 129 (11), 115 (13), 106 (10), 105 (100), 91 (37), 79 (31),

77 (51), 67 (12). HRMS (ESI-TOF): calcd. for C₉H₁₂F₂O₂Na [M

+ Na]⁺213.0703; found 213.0700. Compound 5aB: FTIR (CHCl₃):

m/z (%) = 467 (19) [M + H]⁺, 466 (50) [M]⁺, 317 (20), 161 (29), ν = 1782, 1459, 1252, 1218, 1184, 1118, 1049, 1021, 993, 927 cm^–1.

˜

160 (100), 147 (95), 129 (27), 121 (15), 115 (9), 91 (20), 77 (8).

HRMS (ESI-TOF): calcd. for C₂₇H₂₄F₂O₃SNa [M + Na]⁺

489.1312; found 489.1309.

¹H NMR (500 MHz, CDCl₃): δ = 2.67–2.56 (m, 1 H, CHHCO),

2.52–2.42 (m, 2 H, CHHCO and CHH), 2.38–2.24 (m, 1 H, CH),

2.07–1.94 (m, 3 H, 3ϫ CHH), 1.84–1.73 (m, 1 H, CHH), 1.59–1.49

(m, 1 H, CHH), 1.02 (dd, J = 7.3, 2.1 Hz, 3 H, CH₃) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 175.6 (CO), 127.2 (dd, J = 265.6,

250.4 Hz, CF₂), 89.5 (dd, J = 31.8, 20.3 Hz, C), 38.0 (dd, J = 21.1,

24.6 Hz, CH), 33.0 (d, J = 3.3 Hz, CH₂), 28.2 (CH₂), 27.4 (t, J =

4.1 Hz, CH₂), 26.0 (d, J = 4.3 Hz, CH₂), 14.5 (dd, J = 4.9, 7.4 Hz,

CH₃) ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –102.6 (dd, J =

236.0, 1.41 Hz, 1 F), –126.5 (d, J = 236.0 Hz, 1 F) ppm. MS: m/z

(%) = 191 (9) [M + H]⁺, 171 (5), 151 (69), 123 (8), 111 (33), 95 (4),

83 (22), 65 (3), 55 (32). HRMS (ESI-TOF): calcd. for

C₉H₁₂F₂O₂Na [M + Na]⁺213.0703; found 213.0693.

(E)-Methyl 6-{1-[Difluoro(phenylsulfanyl)methyl]-3-oxo-1,3-di-

hydroisobenzofuran-1-yl}hex-2-enoate (8e): According to general

procedure E, the reaction of 8a (936 mg, 2.6 mmol), methyl acrylate

(1.1 mL, 12 mmol), and Grubbs’ 2^ndgeneration catalyst (64 mg,

75 μmol) in dry CH₂Cl₂(20 mL) gave 8e (989 mg, 79% yield) as a

white solid after purification by column chromatography (SiO₂,

100% hexanes to 10% EtOAc in hexanes) [m.p. 85–86 °C (CH₂Cl₂/

hexanes)]. FTIR (CHCl ): ν = 1781, 1717, 1659, 1468, 1288, 1051,

˜

3

982 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.95 (d, J = 7.6 Hz, 1

1

H, ArH), 7.71 (ddd, J = 7.5, 7.5, 1.3 Hz, 1 H, ArH), 7.63 (ddd, J

= 7.5, 7.5, 0.8 Hz, 1 H, ArH), 7.53 (d, J = 7.7 Hz, 1 H, ArH), 7.48

(d, J = 7.1 Hz, 2 H, 2ϫ ArH), 7.43–7.36 (m, 1 H, ArH), 7.35–7.28

(m, 2 H, 2ϫ ArH), 6.79 (d, J = 15.6, 6.9 Hz, 1 H, CH=CH), 5.74

(dt, J = 15.7, 1.5 Hz, 1 H, CH=CH), 3.70 (s, 3 H, OCH₃), 2.44

(ddd, J = 14.3, 12.1, 4.4 Hz, 1 H, CHH), 2.33–2.08 (m, 3 H, 3ϫ

CHH), 1.45–1.30 (m, 1 H, CHH), 1.95–0.83 (m, 1 H, CHH) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 168.6 (C), 166.7 (C), 147.5 (CH),

145.6 (C), 136.7 (2ϫ CH), 134.6 (CH), 130.6 (CH), 130.1 (CH),

129.0 (2 ϫ CH), 128.2 (t, J = 296.4 Hz, CF₂), 127.2 (C), 126.0

(CH), 125.0 (C), 123.3 (CH), 121.8 (CH), 89.2 (t, J = 28.0 Hz, C),

51.4 (OCH₃), 31.6 (CH₂), 31.4 (CH₂), 21.0 (CH₂) ppm. ¹⁹F NMR

(376 MHz, CDCl₃): δ = –80.9 (d, J = 214.9 Hz, 1 F, CFF), –82.3

(d, J = 214.9 Hz, 1 F, CFF) ppm. MS: m/z (%) = 419 (4) [M +

H]⁺, 418 (3) [M]⁺, 385 (15), 359 (21), 358 (70), 329 (17), 288 (21),

286 (18), 227 (22), 182 (20), 181 (100), 180 (13), 159 (51), 131 (12),

103 (7), 77 (7). HRMS (ESI-TOF): calcd. for C₂₂H₂₀F₂O₄SNa [M

+ Na]⁺441.0948; found 441.0947.

7-Benzyl-6,6-difluoro-1-oxaspiro[4.4]nonan-2-one (5b): According to

general procedure F, radical cyclization of 3b (528 mg, 1.5 mmol)

and purification by column chromatography (SiO₂, 15% CH₂Cl₂

and 2 % EtOAc in hexanes) gave 5bA (less polar; 184 mg, 48%

yield, which contains 1% of 5bB as determined by H NMR spec-

troscopy) as a white solid [m.p. 75–76 °C (CH₂Cl₂/hexanes)] and

1

5bB (more polar; 136 mg, 35% yield) as a white solid [m.p. 72–

73 °C (CH Cl /hexanes)]. Compound 5bA: FTIR (CHCl ): ν =

˜

2

3

1784, 1497, 1456, 1346, 1275, 1224, 1182, 1152, 1089, 1072, 1012,

936 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.26–7.17 (m, 2 H, 2ϫ

ArH), 7.16–7.09 (m, 3 H, 3ϫ ArH), 2.97 (dd, J = 13.8, 5.1 Hz, 1

H, CH), 2.83–2.37 (m, 5 H, 5ϫ CHH), 2.08–1.75 (m, 4 H, 4ϫ

CHH), 1.48–1.35 (m, 1 H, CHH) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 175.6 (CO), 138.9 (C), 128.7 (2ϫ CH), 128.4 (2ϫ

CH), 127.0 (dd, J = 265.6, 249.6 Hz, CF₂), 126.3 (CH), 89.5 (dd,

J = 32.4, 21.3 Hz, C), 42.9 (t, J = 20.9 Hz, CH), 33.0 (d, J = 6.1 Hz,

CH₂), 31.9 (d, J = 4.1 Hz, CH₂), 28.5 (CH₂), 24.7 (d, J = 3.4 Hz,

CH₂), 24.0 (d, J = 8.7 Hz, CH₂) ppm. ¹⁹F NMR (470 MHz,

CDCl₃): δ = –125.2 (dd, J = 230.3, 27.7 Hz, 1 F), –128.6 (dd, J =

230.3, 3.8 Hz, 1 F) ppm. MS: m/z (%) = 267 (14) [M + H]⁺, 266

General Procedure F for the Preparation of γ-gem-Difluoromethyl-

enated Spiro-γ-butyrolactones 5a–m

6,6-Difluoro-7-methyl-1-oxaspiro[4.4]nonan-2-one (5a): Argon was (80) [M]⁺, 247 (8), 246 (26), 227 (13), 226 (66), 209 (1), 208 (5), 167

bubbled through a solution of 3a (451 mg, 1.5 mmol) in dry toluene

(50 mL) for 30 min, and a mixture of Bu₃SnH (0.95 mL, 3 mmol)

and AIBN (37 mg, 0.2 mmol) in dry toluene (8 mL) was added

dropwise at reflux over 1 h. The resulting reaction mixture was

heated at reflux for 8 h and then evaporated to dryness to give a

(85), 166 (42), 117 (72), 115 (72), 115 (33), 111 (10), 109 (5), 91

(100), 77 (16), 65 (28), 50 (10). HRMS (ESI-TOF): calcd. for

C₁₅H₁₆F₂O₂Na [M + Na]⁺289.1016; found 289.1030. Compound

5bB: FTIR (CHCl ): ν = 1787, 1497, 1455, 1254, 1189, 1141, 1096,

˜

3

1

1060, 989 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.26–7.17 (m, 2

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Synthesis of gem-Difluoromethylenated Spiro-γ-butyrolactones

H, 2ϫ ArH), 7.16–7.09 (m, 3 H, 3ϫ ArH), 3.09–2.94 (m, 1 H,

CH), 2.72–2.41 (m, 5 H, 5ϫ CHH), 2.09–1.47 (m, 2 H, 2ϫ CHH),

990 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.87–7.73 (m, 3 H, 3ϫ

ArH), 7.65 (s, 1 H, ArH), 7.53–7.38 (m, 2 H, 2ϫ ArH), 7.34 (dd,

1.84–1.73 (m, 2 H, 2ϫ CHH), 1.72–1.59 (m, 1 H, CHH) ppm. ¹³C J = 8.4, 1.4 Hz, 1 H, ArH), 3.22 (dd, J = 13.7, 4.9 Hz, 1 H, CH),

NMR (125 MHz, CDCl₃): δ = 175.6 (CO), 139.1 (C), 128.8 (2ϫ

CH), 128.5 (2ϫ CH), 127.0 (dd, J = 266.4, 251.6 Hz, CF₂), 126.3

(CH), 89.5 (dd, J = 31.3, 20.0 Hz, C), 44.8 (dd, J = 23.3, 19.6 Hz,

CH), 35.4 (dd, J = 6.5, 4.5 Hz, CH₂), 32.9 (d, J = 3.0 Hz, CH₂),

28.2 (CH₂), 26.0 (d, J = 4.3 Hz, CH₂), 25.6 (d, J = 3.6 Hz, CH₂)

ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –100.9 (dd, J = 235.9,

3.03–2.84 (m, 1 H, CHH), 2.84–2.60 (m, 3 H, 3ϫ CHH), 2.60–2.45

(m, 1 H, CHH), 2.13–1.85 (m, 4 H, 4ϫ CHH), 1.62–1.43 (m, 1 H,

CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 175.5 (CO), 136.4

(C), 133.5 (C), 132.2 (C), 128.1 (CH), 127.6 (CH), 127.4 (CH),

127.1 (CH), 127.0 (dd, J = 262.1, 247.9 Hz, CF₂), 127.0 (CH), 126.1

(CH), 125.4 (CH), 89.6 (dd, J = 32.3, 21.1 Hz, C), 42.8 (t, J =

22.6 Hz, 1 F, CFF), –124.9 (d, J = 235.9 Hz, 1 F, CFF) ppm. MS: 10.2 Hz, CH), 33.2 (d, J = 6.0 Hz, CH₂), 32.0 (d, J = 4.1 Hz, CH₂),

m/z (%) = 267 (19) [M + H]⁺, 266 (66) [M]⁺, 247 (6), 246 (38), 227 28.5 (CH₂), 24.7 (d, J = 3.3 Hz, CH₂), 24.0 (d, J = 8.5 Hz, CH₂)

(11), 226 (79), 209 (2), 208 (3), 167 (91), 166 (38), 117 (68), 115

ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –121.6 (dd, J = 231.0,

(40), 111 (9), 109 (4), 91 (100), 77 (16), 65 (28), 50 (11). HRMS 28.2 Hz, 1 F), –125.5 (d, J = 231.0 Hz, 1 F) ppm. MS: m/z (%) =

(ESI-TOF): calcd. for C₁₅H₁₆F₂O₂Na [M + Na]⁺289.1016; found

289.1013.

317 (5) [M + H]⁺, 316 (33) [M]⁺, 310 (20), 292 (44), 265 (4), 205

(12), 181 (13), 179 (40), 165 (48), 141 (100), 115 (30), 91 (12), 77

(13), 55 (13). HRMS (ESI-TOF): calcd. for C₁₉H₁₈F₂O₂Na [M +

6,6-Difluoro-7-(4-methylbenzyl)-1-oxaspiro[4.4]nonan-2-one (5c):

According to general procedure F, radical cyclization of 3c

(396 mg, 1 mmol) and purification by column chromatography

(SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes) gave 5cA (less po-

lar; 135 mg, 46% yield, which contains 4% of 5cB as determined by

¹H NMR spectroscopy) as a white solid [m.p. 61–62 °C (CH₂Cl₂/

hexanes)] and 5cB (more polar; 104 mg, 35% yield, which contains

4% of 5cA as determined by ¹H NMR spectroscopy) as a white

solid [m.p. 59–60 °C (CH₂Cl₂/hexanes)]. Compound 5cA: FTIR

Na]⁺339.1173; found 339.1175. Compound 5dB: FTIR (CHCl₃):

1

ν = 1784, 1509, 1459, 1188, 1140, 1085, 1056, 990 cm^–1. H NMR

˜

(500 MHz, CDCl₃): δ = 7.87–7.73 (m, 3 H, 3ϫ ArH), 7.66 (s, 1 H,

ArH), 7.53–7.40 (m, 2 H, 2ϫ ArH), 7.34 (d, J = 8.2 Hz, 1 H, ArH),

3.26 (dd, J = 13.4, 4.2 Hz, 1 H, CH), 3.88–2.65 (m, 3 H, 3ϫ CHH),

2.64–2.50 (m, 2 H, 2ϫ CHH), 2.18–2.00 (m, 2 H, 2ϫ CHH), 2.93–

1.70 (m, 3 H, 3ϫ CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

175.5 (CO), 136.5 (C), 133.5 (C), 132.2 (C), 128.1 (CH), 127.6

(CH), 127.5 (CH), 127.3 (d, J = 266.6 Hz, CF₂), 127.3 (CH), 127.1

(CH), 126.1 (CH), 125.4 (CH), 89.6 (dd, J = 31.5, 20.3 Hz, C), 44.7

(dd, J = 23.3, 19.8 Hz, CH), 35.5 (dd, J = 6.1, 4.1 Hz, CH₂), 32.8

(d, J = 2.8 Hz, CH₂), 28.2 (CH₂), 25.9 (d, J = 3.6 Hz, CH₂), 25.6

(t, J = 3.6 Hz, CH₂) ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –99.2

(dd, J = 236.2, 23.5 Hz, 1 F), –123.4 (d, J = 236.2 Hz, 1 F) ppm.

MS: m/z (%) = 317 (8) [M + H]⁺, 316 (31) [M]⁺, 293 (15), 292 (67),

264 (8), 219 (10), 205 (16), 204 (21), 191 (9), 180 (17), 179 (57), 167

(75), 165 (54), 152 (30), 141 (100), 129 (18), 115 (23), 105 (14),

95 (18), 77 (21), 67 (16), 55 (11). HRMS (ESI-TOF): calcd. for

C₁₉H₁₈F₂O₂Na [M + Na]⁺339.1173; found 339.1173.

(CHCl ): ν = 1784, 1516, 1459, 1346, 1183, 1155, 1083, 1013,

˜

3

934 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.90–7.80 (m, 4 H, 4ϫ

ArH), 2.87 (dd, J = 13.5, 5.1 Hz, 1 H, CH), 2.75–2.35 (m, 5 H, 5ϫ

CHH), 2.20 (s, 3 H, CH₃), 2.04–1.75 (m, 4 H, 4ϫ CHH), 1.45–

1.30 (m, 1 H, CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 175.6

(CO), 135.8 (2ϫ C), 129.1 (2ϫ CH), 128.6 (2ϫ CH), 127.0 (dd, J

= 268.5, 252.3 Hz, CF₂), 89.5 (dd, J = 32.1, 20.9 Hz, C), 42.9 (t, J

= 20.9 Hz, CH), 32.6 (d, J = 6.3 Hz, CH), 31.9 (d, J = 3.9 Hz,

CH₂), 28.5 (CH₂), 24.7 (d, J = 3.3 Hz, CH₂), 24.0 (d, J = 8.4 Hz,

CH₂), 20.9 (CH₃) ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –123.2

(dd, J = 231.0, 27.7 Hz, 1 F, CFF), –128.6 (dd, J = 231.0 Hz, 1 F,

CFF) ppm. MS: m/z (%) = 281 (12) [M + H]⁺, 280 (43) [M]⁺, 260

(4), 240 (10), 181 (21), 180 (8), 131 (43), 106 (12), 105 (100), 91

(12), 77 (27). HRMS (ESI-TOF): calcd. for C₁₆H₁₈F₂O₂Na [M +

2,2-Difluoro-3-methyl-3ЈH-spiro[cyclopentane-1,1Ј-isobenzofuran]-

3Ј-one (5e): According to general procedure F, radical cyclization of

3e (522 mg, 1.5 mmol) and purification by column chromatography

(SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes) gave a 1:3 mixture

of diastereoisomers [determined by ¹⁹F NMR spectroscopy

(376 MHz)] of 5e (317 mg, 89% yield) as a colorless liquid: FTIR

Na]⁺303.1173; found 303.1172. Compound 5cB: FTIR (CHCl₃):

1

ν = 1783, 1515, 1459, 1253, 1188, 1142, 1091, 1056, 990 cm^–1. H

˜

NMR (500 MHz, CDCl₃): δ = 7.90–7.80 (m, 4 H, 4ϫ ArH), 2.97

(d, J = 9.0 Hz, 1 H, CH), 2.70–2.57 (m, 1 H, CHH), 2.56–2.40 (m,

4 H, 4ϫ CHH), 2.24 (s, 3 H, CH₃), 2.10–1.93 (m, 2 H, 2ϫ CHH),

1.83–1.72 (m, 2 H, 2ϫ CHH), 1.71–1.54 (m, 1 H, CHH) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 175.5 (CO), 135.9 (C), 135.8 (C),

129.1 (2ϫ CH), 128.7 (2ϫ CH), 127.3 (dd, J = 266.5, 251.8 Hz,

CF₂), 89.4 (dd, J = 31.0, 19.8 Hz, C), 44.8 (dd, J = 23.0, 19.6 Hz,

CH), 34.8 (dd, J = 6.5, 3.8 Hz, CH₂), 32.9 (d, J = 3.0 Hz, CH₂),

28.2 (CH₂), 26.1 (d, J = 4.3 Hz, CH₂), 25.5 (t, J = 3.8 Hz, CH₂),

20.9 (CH₃) ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –101.2 (dd, J

= 235.7, 22.1 Hz, 1 F), –124.9 (d, J = 235.7 Hz, 1 F) ppm. MS:

m/z (%) = 281 (8) [M + H]⁺, 280 (49) [M]⁺, 261 (3), 241 (12), 240

(37), 181 (31), 180 (13), 131 (53), 106 (9), 105 (100), 91 (15), 77 (30).

HRMS (ESI-TOF): calcd. for C₁₆H₁₈F₂O₂Na [M + Na]⁺303.1173;

found 303.1172.

(neat): ν = 1777, 1614, 1467, 1340, 1052, 986 cm^{–1 1}H NMR

.

˜

(500 MHz, CDCl₃, major isomer marked *): δ = 7.90–7.83 (m, 2

H, 2ϫ ArH major and minor), 7.73–7.63 (m, 2 H, 2ϫ ArH major

and minor), 7.60–7.50 (m, 4 H, 4ϫ ArH major and minor), 2.83–

2.65 (m, 1 H, CH, minor), 2.64–2.50 (m, 1 H, CH*), 2.48–2.39 (m,

1 H, CHH minor), 2.38–2.22 (m, 3 H, 2ϫ CHH* and CHH minor),

2.20–2.03 (m, 2 H, 2ϫ CHH major and minor), 1.90–1.73 (m, 1 H,

CHH*), 1.68–1.53 (m, 1 H, CHH minor), 1.21 (dd, J = 7.3, 2.1 Hz,

3 H, CH₃*), 1.14 (d, J = 6.9 Hz, 3 H, CH₃minor) ppm. ¹³C NMR

(125 MHz, CDCl₃, major isomer marked *): δ = 168.5 (CO*), 168.5

(CO minor), 145.2 (C*), 145.0 (C minor), 134.2 (CH minor), 134.1

(CH*), 130.0 (2ϫ CH major and minor), 127.6 (dd, J = 271.4,

248.1 Hz, CF₂*), 126.7 (dd, J = 268.1, 248.6 Hz, CF₂minor), 126.7

(2ϫ C major and minor), 125.4 (2ϫ CH major and minor), 123.9

6,6-Difluoro-7-(naphthalen-2-ylmethyl)-1-oxaspiro[4.4]nonan-2-one (d, J = 4.8 Hz, CH*), 123.9 (d, J = 6.4 Hz, CH minor), 90.6 (dd, J

(5d): According to general procedure F, radical cyclization of 3d

(608 mg, 1.4 mmol) and purification by column chromatography

= 33.1, 21.8 Hz, C*), 90.0 (dd, J = 32.5, 22.1 Hz, C minor), 38.9

(dd, J = 24.0, 20.6 Hz, CH*), 37.1 (t, J = 21.1 Hz, CH minor), 33.2

(SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes) gave 5dA (less po- (d, J = 3.1 Hz, CH₂*), 32.4 (d, J = 2.8 Hz, CH₂minor), 28.3 (t, J

lar; 199 mg, 44% yield) as a white solid [m.p. 106–117 °C (CH₂Cl₂/

hexanes)] and 5dB (more polar; 148 mg, 32% yield) as a white solid

[m.p. 105–106 °C (CH₂Cl₂/hexanes)]. Compound 5dA: FTIR

= 3.9 Hz, CH₂*), 25.9 (d, J = 8.9 Hz, CH₂minor), 15.1 (t, J =

6.4 Hz, CH₃*), 10.8 (d, J = 7.1 Hz, CH₃minor) ppm. ¹⁹F NMR

(376 MHz, CDCl₃, major isomer marked *): δ = –96.1 (dd, J =

236.9, 26.8 Hz, 1 F*), –124.6 (dd, J = 230.3, 28.2 Hz, 1 F minor),

(CHCl ): ν = 1784, 1509, 1459, 1346, 1188, 1140, 1085, 1014,

˜

3

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M. Pohmakotr et al.

FULL PAPER

–124.9 (d, J = 236.9 Hz, 1 F*), –127.2 (d, J = 230.3 Hz, 1 F minor) (C minor), 135.9 (CH*), 135.8 (CH minor), 135.8 (CH*), 135.7 (CH

ppm. MS: m/z (%) = 239 (61) [M + H]⁺, 238 (21), 201 (16), 181

minor), 134.2 (C minor), 134.1 (C*), 130.1 (2 ϫ CH major and

(9), 141 (3), 159 (100), 143 (3), 131 (21), 115 (7), 105 (13), 89 (14). minor), 129.2 (4ϫ CH major and minor), 128.7 (4ϫ CH major and

HRMS (ESI-TOF): calcd. for C₁₃H₁₂F₂O₂Na [M + Na]⁺261.0703;

found 261.0700.

minor), 127.2 (dd, J = 272.1, 249.3 Hz, CF₂*), 127.0 (C minor),

126.8 (C*), 126.6 (dd, J = 270.0, 249.0 Hz, CF₂minor), 125.6

(CH*), 125.5 (CH minor), 123.9 (d, J = 4.5 Hz, CH*), 123.8 (d, J

= 4.3 Hz, CH minor), 90.8 (dd, J = 32.9, 21.6 Hz, C*), 90.2 (dd, J

= 37.5, 25.0 Hz, C minor), 45.8 (dd, J = 23.3, 19.1 Hz, CH*), 44.1

(dd, J = 20.4, 20.4 Hz, CH minor), 35.3 (dd, J = 5.6, 5.6 Hz, CH₂*),

33.1 (d, J = 2.9 Hz, CH*), 32.6 (d, J = 6.1 Hz, CH minor), 32.1 (d,

J = 2.5 Hz, CH₂minor), 26.3 (dd, J = 3.3, 3.3 Hz, CH₂*), 24.3 (d,

J = 8.1 Hz, CH₂minor), 20.9 (2ϫ CH₃minor) ppm. ¹⁹F NMR

(376 MHz, CDCl₃, major isomer marked *): δ = –94.7 (dd, J =

238.6, 26.7 Hz, 1 F*), –122.6 (dd, J = 230.9, 27.4 Hz, 1 F minor),

–123.7 (d, J = 238.6 Hz, 1 F*), –125.4 (d, J = 230.9 Hz, 1 F minor)

ppm. MS: m/z (%) = 329 (67) [M + H]⁺, 328 (54) [M]⁺, 197 (21),

133 (15), 132 (100), 117 (15), 105 (66), 103 (18), 91 (8), 77 (28).

HRMS (ESI-TOF): calcd. for C₂₀H₁₈F₂O₂Na [M + Na]⁺351.1173;

found 351.1176.

3-Benzyl-2,2-difluoro-3ЈH-spiro[cyclopentane-1,1Ј-isobenzofuran]-

3Ј-one (5f): According to general procedure F, radical cyclization of

3f (635 mg, 1.5 mmol) and purification by column chromatography

(SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes) gave a 1:1.6 mix-

ture of diastereoisomers [determined by ¹⁹F NMR spectroscopy

(376 MHz)] of 5f (388 mg, 82% yield) as a colorless liquid: FTIR

(neat): ν = 1773, 1615, 1467, 1347, 1042, 987 cm^{–1 1}H NMR

.

˜

(500 MHz, CDCl₃, major isomer marked *): δ = 7.97 (d, J = 7.5 Hz,

1 H, ArH*), 7.94 (d, J = 7.7 Hz, 1 H, ArH* minor), 7.80–7.70 (m,

2 H, 2ϫ ArH major and minor), 7.68–7.57 (m, 4 H, 4ϫ ArH major

and minor), 7.40–7.33 (m, 4 H, 4ϫ ArH major and minor), 7.32–

7.20 (m, 6 H, 6ϫ ArH major and minor), 3.22 (dd, J = 13.5, 4.2 Hz,

1 H, CH*), 3.16 (dd, J = 13.6, 5.1 Hz, 1 H, CH minor), 3.13–2.98

(m, 1 H, CH*), 2.96–2.74 (m, 2 H, 2ϫ CHH major and minor),

2.75 (dd, J = 13.5, 10.0 Hz, 1 H, CHH minor), 2.58–2.45 (m, 1 H, 2,2-Difluoro-3-(3-methoxybenzyl)-3ЈH-spiro[cyclopentane-1,1Ј-iso-

CHH minor), 2.44–2.30 (m, 1 H, CHH*), 2.25–2.14 (m, 3 H, CHH benzofuran]-3Ј-one (5h): According to general procedure F, radical

major and 2ϫ CHH minor), 2.14–2.06 (m, 1 H, CHH*), 2.06–1.95

cyclization of 3h (635 mg, 1.5 mmol) and purification by column

(m, 1 H, CHH*), 1.85–1.73 (m, 1 H, CHH minor) ppm. ¹³C NMR chromatography (SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes)

(125 MHz, CDCl₃, major isomer marked *): δ = 168.6 (CO*), 168.5

(CO minor), 145.0 (C*), 144.8 (C minor), 139.1 (C*), 138.8 (C

gave a 1:1.6 mixture of diastereoisomers [determined by ¹⁹F NMR

spectroscopy (376 MHz)] of 5h (489 mg, 85% yield) as a colorless

minor), 134.2 (2ϫ CH major and minor), 130.0 (2ϫ CH major and liquid. FTIR (neat): ν = 1778, 1601, 1585, 1491, 1467, 1262, 1041,

˜

1

minor), 128.9 (2ϫ CH major and minor), 128.7 (2ϫ CH major and

minor), 128.5 (4ϫ CH major and minor), 126.4 (CH minor), 126.3

987 cm^–1. H NMR (400 MHz, CDCl₃, major isomer marked *): δ

= 7.88–7.77 (m, 2 H, 2ϫ ArH major and minor), 7.68–7.58 (m, 2

(CH*), 125.7 (CH*), 125.6 (CH minor), 127.2 (dd, J = 273.0, H, 2ϫ ArH major and minor), 7.57–7.45 (m, 4 H, 4ϫ ArH major

249.3 Hz, CF₂*), 126.6 (dd, J = 269.4, 248.4 Hz, CF₂minor), 127.1

(C*), 126.9 (C minor), 124.0 (d, J = 3.6 Hz, CH*), 123.9 (d, J =

3.5 Hz, CH minor), 90.8 (dd, J = 33.0, 21.6 Hz, C*), 90.1 (dd, J =

and minor), 7.20–7.02 (m, 2 H, 2ϫ ArH major and minor), 6.80–

6.61 (m, 6 H, 6ϫ ArH major and minor), 3.72 (s, 6 H, 2ϫ OCH₃

major and minor), 3.14–2.98 (m, 2 H, 2ϫ ArH major and minor),

32.0, 21.8 Hz, C minor), 45.8 (dd, J = 23.3, 19.0 Hz, CH*), 44.1 2.98–2.85 (m, 1 H, CH*), 2.85–2.64 (m, 2 H, CHH* and CH

(dd, J = 20.5, 20.5 Hz, CH minor), 35.8 (t, J = 5.8 Hz, CH*), 33.2 minor), 2.60 (dd, J = 13.5, 10.3 Hz, 1 H, CHH minor), 2.46–2.32

(d, J = 3.0 Hz, CH*), 33.1 (d, J = 6.3 Hz, CH₂*), 32.1 (d, J = (m, 1 H, CHH minor), 2.32–2.18 (m, 1 H, CHH*), 2.14–1.81 (m, 5

3.1 Hz, CH₂*), 26.4 (t, J = 3.5 Hz, CH₂*), 24.4 (d, J = 8.1 Hz, CH₂H, 3ϫ CHH* and 2ϫ CHH minor), 1.75–1.58 (m, 1 H, CHH

minor) ppm. ¹⁹F NMR (376 MHz, CDCl₃, major isomer marked minor) ppm. ¹³C NMR (100 MHz, CDCl₃, major isomer marked

*): δ = –94.6 (dd, J = 238.8, 23.3 Hz, 1 F*), –122.7 (dd, J = 232.0,

27.5 Hz, 1 F minor), –124.8 (d, J = 238.8 Hz, 1 F*), –125.5 (d, J =

232.0 Hz, 1 F minor) ppm. MS: m/z (%) = 315 (69) [M + H]⁺, 314

*): δ = 168.6 (CO*), 168.5 (CO minor), 160.0 (2ϫ C major and

minor), 144.9 (C*), 144.7 (C minor), 140.6 (C*), 140.3 (C minor),

134.3 (CH minor), 134.2 (CH*), 130.1 (2ϫ CH major and minor),

(21) [M]⁺, 223 (4), 197 (41), 177 (9), 159 (12), 129 (7), 118 (100), 129.4 (2ϫ CH major and minor), 127.1 (dd, J = 272.0, 249.0 Hz,

117 (20), 115 (8), 91 (31), 77 (13), 65 (10). HRMS (ESI-TOF):

CF₂*), 126.5 (dd, J = 270.0, 249.0 Hz, CF₂minor), 126.9 (C minor),

126.7 (C*), 125.6 (CH*), 125.6 (CH minor), 124.0 (d, J = 5.0 Hz,

CH*), 123.9 (d, J = 4.0 Hz, CH minor), 121.1 (CH*), 121.0 (CH

minor), 114.5 (CH*), 114.2 (CH minor), 111.7 (2ϫ CH major and

minor), 90.3 (dd, J = 33.0, 22.0 Hz, C*), 90.1 (dd, J = 32.0, 22.0 Hz,

C minor), 55.1 (2ϫ OCH₃major and minor), 45.6 (dd, J = 24.0,

19.0 Hz, CH*), 43.9 (dd, J = 20.0, 20.0 Hz, CH minor), 35.8 (dd,

J = 6.0, 6.0 Hz, 2ϫ CH major and minor), 33.1 (d, J = 4.0 Hz,

CH*), 32.0 (d, J = 3.0 Hz, CH₂minor), 26.3 (d, J = 3.0 Hz, CH₂*),

24.3 (d, J = 8.0 Hz, CH₂minor) ppm. ¹⁹F NMR (376 MHz, CDCl₃,

major isomer marked *): δ = –94.6 (dd, J = 238.2, 27.1 Hz, 1 F*),

–122.7 (dd, J = 230.0, 27.5 Hz, 1 F minor), –123.8 (d, J = 238.2 Hz,

1 F*), –125.6 (d, J = 230.0 Hz, 1 F minor) ppm. MS: m/z (%) =

345 (69) [M + H]⁺, 344 (21) [M]⁺, 287 (9), 178 (8), 149 (19), 148

(10), 123 (50), 91 (13) cm^–1. HRMS (ESI-TOF): calcd. for

C₂₀H₁₈F₂O₃Na [M + Na]⁺367.1122; found 367.1120.

calcd. for C₁₉H₁₆F₂O₂Na [M + Na]⁺337.1016; found 337.1017.

2,2-Difluoro-3-(4-methylbenzyl)-3ЈH-spiro[cyclopentane-1,1Ј-iso-

benzofuran]-3Ј-one (5g): According to general procedure F, radical

cyclization of 3g (656 mg, 1.5 mmol) and purification by column

chromatography (SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes)

gave a 1:1.6 mixture of diastereoisomers [determined by ¹⁹F NMR

spectroscopy (376 MHz)] of 5g (407 mg, 83% yield) as a colorless

liquid. FTIR (neat): ν = 1779, 1614, 1468, 1345, 1041, 983 cm^–1.

˜

¹H NMR (500 MHz, CDCl₃, major isomer marked *): δ = 7.83 (d,

J = 7.6 Hz, 1 H, ArH*), 7.80 (d, J = 7.7 Hz, 1 H, ArH minor),

7.65–7.58 (m, 2 H, 2ϫ ArH major and minor), 7.55–7.45 (m, 4 H,

4ϫ ArH major and minor), 7.25–7.10 (m, 4 H, 4ϫ ArH minor),

7.08–6.98 (m, 4 H, 4ϫ ArH*), 3.05 (dd, J = 13.1, 3.7 Hz, 1 H,

CHH*), 2.99 (dd, J = 13.5, 5.0 Hz, 1 H, CHH minor), 2.98–2.83

(m, 1 H, CH*), 2.80–2.62 (m, 2 H, CHH major and CH minor),

2.59 (dd, J = 13.5, 9.9 Hz, 1 H, CHH minor), 2.45–2.33 (m, 1 H, 2,2-Difluoro-3-methyl-3ЈH-spiro[cyclohexane-1,1Ј-isobenzofuran]-3Ј-

CHH minor), 2.30–2.18 (m, 7 H, CHH*, 2 ϫ CH₃major and

minor), 2.12–2.01 (m, 3 H, CHH major and 2ϫ CHH minor), 2.01–

1.93 (m, 1 H, CHH*), 1.93–1.80 (m, 1 H, CHH*), 1.72–1.58 (m, 1

one (5i): According to general procedure F, radical cyclization of

8a (528 mg, 1.5 mmol) and purification by column chromatography

(SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes) gave 5iA (less po-

H, CHH minor) ppm. ¹³C NMR (125 MHz, CDCl₃, major isomer lar; 184 mg, 48% yield) as a white solid [m.p. 104–105 °C (CH₂Cl₂/

marked *): δ = 168.6 (CO*), 168.4 (CO minor), 145.0 (C*), 144.7 hexanes)] and 5iB (more polar; 136 mg, 35% yield, which contains

12

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Synthesis of gem-Difluoromethylenated Spiro-γ-butyrolactones

1% of 5iA as determined by ¹H NMR spectroscopy) as a white

solid [m.p. 102–103 °C (CH₂Cl₂/hexanes)]. Compound 5iA: FTIR

7.6, 1.1 Hz, 1 H, ArH), 7.65 (ddd, J = 7.6, 0.8, 0.8 Hz, 1 H, ArH),

7.61 (ddd, J = 7.5, 7.5, 0.2 Hz, 1 H, ArH), 7.35–7.28 (m, 2 H, 2ϫ

(CHCl ): ν = 1773, 1467, 1272, 1226, 1087, 1013, 960 cm^–1. ¹H ArH), 7.25–7.18 (m, 3 H, 3ϫ ArH), 3.11 (dd, J = 14.1, 3.3 Hz, 1

˜

3

NMR (400 MHz, CDCl₃): δ = 7.92 (d, J = 7.6 Hz, 1 H, ArH), 7.72 H, CHH), 3.00 (dd, J = 11.6, 11.6 Hz, 1 H, CHH), 2.60–2.45 (m,

(dd, J = 7.4, 7.4 Hz, 1 H, ArH), 7.66–7.54 (m, 2 H, 2ϫ ArH),

2.54–2.35 (m, 1 H, CH), 2.34–2.20 (m, 1 H, CHH), 2.02–1.71 (m,

4 H, 4ϫ CHH), 1.66–1.45 (m, 1 H, CHH), 1.11 (d, J = 6.8 Hz, 3

H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 169.1 (CO), 147.5

(C), 134.2 (CH), 130.0 (CH), 126.5 (C), 125.7 (CH), 123.5 (d, J =

5.0 Hz, CH), 121.4 (dd, J = 256.0, 244.0 Hz, CF₂), 85.5 (dd, J =

34.0, 34.0 Hz, C), 35.5 (dd, J = 21.4, 21.4 Hz, CH), 34.4 (d, J =

3.0 Hz, CH₂), 30.4 (d, J = 8.0 Hz, CH₂), 20.5 (CH₂), 12.2 (t, J =

4.0 Hz, CH₃) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –118.1 (d, J

= 247.8 Hz, 1 F), –124.6 (dd, J = 247.8, 28.3 Hz, 1 F) ppm. MS:

1 H, CH), 2.28–2.15 (m, 1 H, CHH), 2.14–1.98 (m, 2 H, 2ϫ CHH),

1.80–1.65 (m, 3 H, 3ϫ CHH) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 169.0 (CO), 147.8 (C), 139.8 (C), 134.2 (CH), 130.1 (CH), 129.2

(2ϫ CH), 128.5 (2ϫ CH), 126.7 (C), 126.3 (CH), 125.9 (CH), 123.8

(d, J = 3.3 Hz, CH), 120.9 (dd, J = 258.4, 242.8 Hz, CF₂), 85.4

(dd, J = 31.9, 23.0 Hz, C), 43.9 (dd, J = 20.8, 20.8 Hz, CH), 34.8

(d, J = 2.6 Hz, CH₂), 32.5 (d, J = 5.0 Hz, CH₂), 24.7 (d, J = 5.0 Hz,

CH₂), 17.1 (CH₂) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –100.0

to –109.0 (br s, 1 F), –114.0 to –119.0 (br d, J = 251.9 Hz, 1 F)

ppm. MS: m/z (%) = 329 (50) [M + H]⁺, 328 (100) [M]⁺, 308 (21),

m/z (%) = 253 (68) [M + H]⁺, 252 (63) [M]⁺, 212 (10), 160 (15), 270 (13), 199 (16), 172 (18), 169 (16), 159 (18), 147 (19), 131 (14),

159 (100), 146 (53), 131 (31), 104 (10), 103 (19). HRMS (ESI-TOF):

129 (16), 91 (30), 111 (9), 109 (4), 91 (100), 77 (16), 65 (28), 50

calcd. for C₁₄H₁₄F₂O₂Na [M + Na]⁺275.0860; found 275.0854.

(11). C₂₀H₁₈F₂O₂Na [M + Na]⁺351.1173; found 351.1170.

Compound 5iB: FTIR (CHCl ): ν = 1773, 1468, 1272, 1087, 1013,

˜

3

2,2-Difluoro-3-(4-methylbenzyl)-3ЈH-spiro[cyclohexane-1,1Ј-iso-

benzofuran]-3Ј-one (5k): According to general procedure F, radical

cyclization of 8c (680 mg, 1.5 mmol) and purification by column

chromatography (SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes)

gave 5kA (less polar; 323 mg, 63% yield) as a white solid [m.p.

106–107 °C (CH₂Cl₂/hexanes)] and 5kB (more polar; 123 mg, 24%

yield) as a white solid [m.p. 105–107 °C (CH₂Cl₂/hexanes)]. Com-

960 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.91 (d, J = 7.6 Hz, 1

1

H, ArH), 7.69 (ddd, J = 7.4, 7.4, 1.1 Hz, 1 H, ArH), 7.63 (ddd, J

= 7.1, 0.9, 0.9 Hz, 1 H, ArH), 7.58 (ddd, J = 7.5, 1.0, 1.0 Hz, 1 H,

ArH), 2.50–2.37 (m, 1 H, CHH), 2.20–2.09 (m, 1 H, CHH), 2.08–

1.93 (m, 3 H, 3ϫ CHH), 1.80–1.63 (m, 2 H, 2ϫ CHH), 1.25 (d, J

= 6.8 Hz, 3 H, CH₃) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 169.0

(CO), 147.8 (C), 134.0 (CH), 130.0 (CH), 126.6 (C), 125.8 (CH),

123.6 (d, J = 4.0 Hz, CH), 121.1 (dd, J = 257.3, 242.5 Hz, CF₂),

86.1 (dd, J = 31.0, 22.9 Hz, C), 36.4 (dd, J = 21.8, 21.8 Hz, CH),

34.7 (2ϫ CH₂), 28.9 (d, J = 5.8 Hz, CH₂), 17.3 (CH₂), 12.9 (dd, J

= 7.8, 3.4 Hz, CH₃) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –100.0

to –112.0 (br s, 1 F), –114.0 to –121.0 (br d, J = 205.7 Hz, 1 F)

ppm. MS: m/z (%) = 253 (41) [M + H]⁺, 252 (65) [M]⁺, 160 (13),

159 (100), 146 (69), 131 (36), 105 (12), 103 (23), 77 (8). HRMS

(ESI-TOF): calcd. for C₁₄H₁₄F₂O₂Na [M + Na]⁺275.0860; found

275.0865.

pound 5kA: FTIR (CHCl ): ν = 1773, 1601, 1515, 1468, 1289,

˜

3

1251, 1172, 1059, 975 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.81

(d, J = 7.5 Hz, 1 H, ArH), 7.65–7.57 (m, 1 H, ArH), 7.56–7.44 (m,

2 H, 2ϫ ArH), 7.06–6.95 (m, 4 H, 4ϫ ArH), 3.05 (dd, J = 12.7,

2.1 Hz, 1 H, CHH), 2.54–2.29 (m, 2 H, CH, CHH), 2.28–2.06 (m,

4 H, CH₃, CHH), 1.83–1.53 (m, 4 H, 4ϫ CHH), 1.41–1.24 (m, 1

H, CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 169.0 (CO),

147.3 (C), 135.7 (2ϫ C), 134.2 (CH), 130.0 (CH), 129.1 (4ϫ CH),

126.4 (C), 125.6 (CH), 123.5 (d, J = 4.0 Hz, CH), 121.3 (dd, J =

257.0, 245.0 Hz, CF₂), 85.4 (dd, J = 33.0, 23.0 Hz, C), 42.5 (dd, J

= 20.0, 20.0 Hz, CH), 34.5 (d, J = 3.0 Hz, CH₂), 32.5 (CH₂), 27.0

(d, J = 7.0 Hz, CH₂), 21.3 (CH₃), 20.2 (CH₂) ppm. ¹⁹F NMR

(376 MHz, CDCl₃): δ = –117.5 (d, J = 247.6 Hz, 1 F), –122.0 (dd,

J = 247.6, 27.8 Hz, 1 F) ppm. MS: m/z (%) = 343 (34) [M + H]⁺,

342 (95) [M]⁺, 322 (56), 302 (19), 199 (20), 106 (24), 105 (100), 103

(22), 79 (15), 77 (21). HRMS (ESI-TOF): calcd. for C₂₁H₂₀F₂O₂Na

[M + Na]⁺365.1329; found 365.1323. Compound 5kB: FTIR

2,2-Difluoro-3-benzyl-3ЈH-spiro[cyclohexane-1,1Ј-isobenzofuran]-3Ј-

one (5j): According to general procedure F, radical cyclization of

8b (658 mg, 1.5 mmol) and purification by column chromatography

(SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes) gave 5jA (less po-

lar; 335 mg, 68% yield) as a white solid [m.p. 107–108 °C (CH₂Cl₂/

hexanes)] and 5jB (more polar; 113 mg, 23% yield) as a white solid

[m.p. 109–110 °C (CH₂Cl₂/hexanes)]. Compound 5jA: FTIR

(CHCl ): ν = 1773, 1601, 1515, 1468, 1289, 1251, 1117, 1086, 1058,

˜

(CHCl ): ν = 1773, 1496, 1468, 1271, 1081, 1024, 1004, 967 cm^–1.

3

˜

3

1

975 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 7.7 Hz, 1

¹H NMR (500 MHz, CDCl₃): δ = 7.92 (d, J = 7.7 Hz, 1 H, ArH),

7.72 (ddd, J = 7.5, 7.5, 1.0 Hz, 1 H, ArH), 7.63 (dd, J = 7.7, 2.4 Hz,

1 H, ArH), 7.60 (ddd, J = 7.5, 7.5, 0.8 Hz, 1 H, ArH), 7.35–7.28

(m, 2 H, 2ϫ ArH), 7.26–7.18 (m, 3 H, 3ϫ ArH), 3.19 (dd, J =

3.1, 2.9 Hz, 1 H, CHH), 2.65–2.46 (m, 1 H, CHH), 2.48 (dd, J =

13.3, 10.6 Hz, 1 H, CHH), 2.35–2.20 (m, 1 H, CHH), 1.93–1.84

(m, 1 H, CHH), 1.84–1.68 (m, 3 H, 3ϫ CHH), 1.50–1.38 (m, 1 H,

CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 169.0 (CO), 147.4

(C), 138.9 (C), 134.2 (CH), 130.1 (CH), 129.2 (2ϫ CH), 128.4 (2ϫ

CH), 126.5 (C), 126.3 (CH), 125.7 (CH), 123.5 (d, J = 27.9 Hz,

CH), 121.3 (dd, J = 256.6, 245.0 Hz, CF₂), 85.4 (dd, J = 33.0,

23.5 Hz, C), 42.4 (dd, J = 21.3, 19.8 Hz, CH), 34.6 (d, J = 3.6 Hz,

CH₂), 33.1 (d, J = 5.8 Hz, CH₂), 27.1 (d, J = 6.9 Hz, CH₂), 20.3

(CH₂) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –117.5 (d, J =

247.6 Hz, 1 F), –122.0 (dd, J = 247.6, 27.8 Hz, 1 F) ppm. MS: m/z

(%) = 329 (94) [M + H]⁺, 328 (100) [M]⁺, 310 (24), 308 (27), 270

(24), 199 (22), 172 (28), 169 (27), 159 (21), 147 (22), 91 (38). HRMS

(ESI-TOF): calcd. for C₂₀H₁₈F₂O₂Na [M + Na]⁺351.1173; found

H, ArH), 7.71 (ddd, J = 7.8, 7.8, 1.0 Hz, 1 H, ArH), 7.67–7.55 (m,

2 H, 2ϫ ArH), 7.16–7.05 (m, 4 H, 4ϫ ArH), 3.06 (dd, J = 14.1,

3.2 Hz, 1 H, ArCHH), 2.95 (dd, J = 11.5, 11.5 Hz, 1 H, ArCHH),

2.57–2.42 (m, 1 H, CH), 2.33 (s, 3 H, CH₃), 2.26–2.14 (m, 1 H,

CHH), 2.13–1.95 (m, 2 H, 2 ϫ CHH), 1.84–1.63 (m, 3 H, 3 ϫ

CHH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 169.0 (CO), 147.8

(C), 136.7 (C), 135.8 (C), 134.2 (CH), 130.1 (CH), 129.2 (2ϫ CH),

129.1 (2ϫ CH), 126.6 (C), 125.9 (CH), 123.7 (d, J = 4.0 Hz, CH),

121.0 (dd, J = 258.0, 243.0 Hz, CF₂), 86.0 (dd, J = 23.0, 23.0 Hz,

C), 44.0 (dd, J = 21.0, 21.0 Hz, CH), 34.8 (CH₂), 32.0 (d, J =

4.0 Hz, CH₂), 24.7 (d, J = 4.0 Hz, CH₂), 21.0 (CH₃), 17.1 (CH₂)

ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –101.0 to –109 (br s, 1 F),

–114.0 to –118.0 (br d, J = 251.9 Hz, 1 F) ppm. MS: m/z (%) =

343 (24) [M + H]⁺, 342 (94) [M]⁺, 322 (53), 199 (19), 106 (24), 105

(100), 77 (25). HRMS (ESI-TOF): calcd. for C₂₁H₂₀F₂O₂Na [M +

Na]⁺365.1329; found 365.1329.

2,2-Difluoro-3-(3-methoxybenzyl)-3ЈH-spiro[cyclohexane-1,1Ј-iso-

benzofuran]-3Ј-one (5l): According to general procedure F, radical

cyclization of 8d (702 mg, 1.5 mmol) and purification by column

chromatography (SiO₂, 15% CH₂Cl₂and 2% EtOAc in hexanes)

351.1178. Compound 5jB: FTIR (CHCl ): ν = 1773, 1496, 1468,

˜

3

1270, 1081, 1025, 1004, 967 cm^–1. H NMR (500 MHz, CDCl₃): δ

1

= 7.95 (ddd, J = 8.4, 0.8, 0.8 Hz, 1 H, ArH), 7.72 (ddd, J = 7.6,

Eur. J. Org. Chem. 0000, 0–0

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M. Pohmakotr et al.

FULL PAPER

gave 5lA (less polar; 344 mg, 64% yield) as a colorless viscous oil

and 5lB (more polar; 102 mg, 19% yield) as a colorless viscous oil.

256.5, 244.0 Hz, CF₂*), 120.3 (dd, J = 257.6, 243.0 Hz, CF₂minor),

85.5 (dd, J = 31.9, 22.9 Hz, C minor), 84.9 (dd, J = 32.9, 23.0 Hz,

C*), 51.8 (2ϫ CH₃major and minor), 38.1 (dd, J = 24.0, 20.3 Hz,

Compound 5lA: FTIR (CHCl ): ν = 1778, 1601, 1467, 1264, 1079,

˜

3

1

1024, 1004, 965 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.92 (d, J CH minor), 37.7 (dd, J = 20.5, 20.5 Hz, CH*), 34.4 (d, J = 3.0 Hz,

= 7.6 Hz, 1 H, ArH), 7.72 (ddd, J = 7.6, 7.6, 1.5 Hz, 1 H, ArH),

2ϫ CH₂major and minor), 32.7 (CH₂*), 31.7 (d, J = 7.8 Hz, CH₂

7.63 (dd, J = 7.6, 2.3 Hz, 1 H, ArH), 7.60 (ddd, J = 7.7, 7.7, 0.7 Hz, minor), 28.1 (d, J = 6.8 Hz, CH₂*), 26.3 (d, J = 4.8 Hz, CH₂minor),

1 H, ArH), 7.23 (dd, J = 7.8, 7.8 Hz, 1 H, ArH), 6.83–6.70 (m, 3

H, 3ϫ ArH), 3.82 (s, 3 H, OCH₃), 3.16 (dd, J = 13.3, 3.2 Hz, 1 H,

CHH), 2.65–2.48 (m, 1 H, CH), 2.45 (dd, J = 13.2, 10.8 Hz, 1 H,

20.1 (CH₂*), 17.0 (CH₂minor) ppm. ¹⁹F NMR (376 MHz, CDCl₃,

major isomer marked *): δ = –104.0 to –110.0 (br s, 1 F minor),

–115.0 to –117.5 (br d, J = 252.3 Hz, 1 F minor), –117.3 (d, J =

CHH), 2.85–2.20 (m, 1 H, CHH), 1.93–1.84 (m, 1 H, CHH), 1.84– 249.3 Hz, 1 F*), –121.6 (dd, J = 249.3, 31.2 Hz, 1 F*) ppm. MS:

1.67 (m, 3 H, 3ϫ CHH), 1.50–1.40 (m, 1 H, CHH) ppm. ¹³C NMR m/z (%) = 311 (20) [M + H]⁺, 310 (100) [M]⁺, 279 (25), 278 (54),

(125 MHz, CDCl₃): δ = 169.0 (CO), 159.7 (C), 147.4 (C), 140.5 (C), 270 (27), 258 (22), 233 (21), 199 (24), 172 (40), 144 (17) cm^–1.

134.2 (CH), 130.1 (CH), 129.4 (CH), 126.5 (C), 125.7 (CH), 123.5

(d, J = 3.8 Hz, CH), 121.7 (CH), 121.3 (dd, J = 256.5, 244.5 Hz,

CF₂), 114.8 (CH), 111.8 (CH), 85.5 (dd, J = 33.1, 23.1 Hz, C), 55.2

(CH₃), 42.4 (dd, J = 19.8, 19.8 Hz, CH), 34.6 (d, J = 3.3 Hz, CH₂),

33.2 (dd, J = 3.1, 3.1 Hz, CH₂), 27.2 (d, J = 6.9 Hz, CH₂), 20.3

(CH₂) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –123.2 (dd, J =

231.0, 27.7 Hz, 1 F), –128.6 (dd, J = 231.0 Hz, 1 F) ppm. MS: m/z

(%) = 359 (30) [M + H]⁺, 358 (100) [M]⁺, 199 (15), 122 (36), 91 (11).

HRMS (ESI-TOF): calcd. for C₂₁H₂₀F₂O₃Na [M + Na]⁺381.1278;

HRMS (ESI-TOF): calcd. for C₁₆H₁₆F₂O₄Na [M + Na]⁺333.0914;

found 333.0914.

Supporting Information (see footnote on the first page of this arti-

cle): Copies of ¹H and ¹³C NMR spectra for all reported com-

pounds.

Acknowledgments

found 381.1279. Compound 5lB: FTIR (CHCl ): ν = 1779, 1601,

˜

3

The authors acknowledge financial support from the Thailand Re-

search Fund (BRG5380019), the Office of the Higher Education

Commission and Mahidol University under the National Research

Universities Initiative, Thailand, and the Center of Excellence for

Innovation in Chemistry (PERCH-CIC), Thailand.

1585, 1489, 1467, 1264, 1079, 1004, 965 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 7.94 (ddd, J = 7.6, 0.9, 0.9 Hz, 1 H, ArH), 7.72 (ddd,

J = 7.3, 7.3, 1.1 Hz, 1 H, ArH), 7.65 (ddd, J = 7.8, 0.9, 0.9 Hz, 1

H, ArH), 7.61 (ddd, J = 7.5, 0.9, 0.9 Hz, 1 H, ArH) 7.23 (dd, J =

7.8, 7.8 Hz, 1 H, ArH), 6.84–6.73 (m, 3 H, 3ϫ ArH), 3.81 (s, 3 H,

OCH₃), 3.09 (dd, J = 14.0, 3.1 Hz, 1 H, CHH), 2.98 (dd, J = 11.7,

11.7 Hz, 1 H, CHH), 2.63–2.45 (m, 1 H, CH), 2.30–2.13 (m, 1 H,

CHH), 2.12–1.75 (m, 2 H, 2ϫ CHH), 1.88–1.63 (m, 3 H, 3ϫ

CHH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 168.9 (CO), 159.8

(C), 147.7 (C), 141.4 (C), 134.2 (CH), 130.1 (CH), 129.5 (CH),

126.6 (C), 125.9 (CH), 123.7 (d, J = 4.1 Hz, CH), 121.5 (CH), 120.9

(dd, J = 257.9, 242.9 Hz, CF₂), 115.0 (CH), 111.6 (CH), 85.4 (dd,

J = 31.8, 23.0 Hz, C), 55.2 (CH₃), 43.7 (dd, J = 20.8, 20.8 Hz, CH),

34.8 (d, J = 2.0 Hz, CH₂), 32.5 (dd, J = 7.1, 2.9 Hz, CH₂), 24.8 (d,

J = 4.6 Hz, CH₂), 17.0 (CH₂) ppm. ¹⁹F NMR (376 MHz, CDCl₃):

δ = –100.0 to –109.0 (br s, 1 F), –114.0 to –118.0 (dd, J = 253.1 Hz,

1 F) ppm. MS: m/z (%) = 359 (29) [M + H]⁺, 358 (100) [M]⁺,

199 (14), 122 (44), 121 (11), 91 (11). HRMS (ESI-TOF): calcd. for

C₂₁H₂₀F₂O₃Na [M + Na]⁺381.1278; found 381.1275.

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furan]-3-yl)acetate (5m): According to general procedure F, radical

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˜

2

3

1614, 1601, 1467, 1439, 1291, 1257, 1172, 1085, 1067, 978 cm^–1. ¹H

NMR (500 MHz, CDCl₃, major isomer marked *): δ = 7.95–7.85

(m, 2 H, 2ϫ ArH major and minor), 7.75–7.68 (m, 2 H, 2ϫ ArH

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14

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Published Online: ᭿

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Date: 12-09-13 17:13:17

Pages: 16

M. Pohmakotr et al.

FULL PAPER

Organofluorine Compounds

A. Chatupheeraphat, D. Soorukram,

C. Kuhakarn, P. Tuchinda, V. Reutrakul,

C. Pakawatchai, S. Saithong,

M. Pohmakotr* ............................... 1–16

Synthesis of gem-Difluoromethylenated

Spiro-γ-butyrolactones by Employing

PhSCF₂Si(CH₃)₃as a gem-Difluoromethyl-

enating Agent

PhSCF₂TMS (TMS = trimethylsilyl) is util-

ized as a gem-difluoromethylenating agent

for the synthesis of gem-difluoromethylen-

ated spiro-γ-butyrolactones.

Keywords: Lactones / Difluoromethylen-

ation / Cyclization / Fluorine

16

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Article Doi

Synthesis of gem-difluoromethylenated spiro-γ-butyrolactones by employing PhSCF2Si(CH3)3 as a gem-difluoromethylenating agent

DOI: 10.1002/ejoc.201300998

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Article abstract of DOI:10.1002/ejoc.201300998

Full text of DOI:10.1002/ejoc.201300998

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