4-methoxybenzyl 3-(2-bromo-4,5-dimethoxyphenyl)propanoate (247)

MeO MeO

CO₂H

t-BuOH, 23 °C

MeO MeO

CO₂t-Bu

244 246

Br Br

Boc₂O DMAP (30 mol %)

MeO

MeO

CO₂H

DMF, 45 °C

MeO

MeO

CO₂PMB

244 247

Br Br

PMBCl NaHCO₃

aryl bromide 244 (500 mg, 1.73 mmol), sodium bicarbonate (291 mg, 3.46 mmol), para- methoxybenzyl chloride (258 μL, 1.90 mmol), and DMF (1 mL). The mixture was stirred under nitrogen at 45 °C for 29 hours. Upon completion (as determined by TLC analysis), the mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed with water (2 x 10 mL) and brine (1 x 10 mL), dried over sodium sulfate, and filtered and evaporated to give the crude product as a yellow oil. The oil was purified by silica gel column chromatography (9:1 hexanes:EtOAc) to give ester 247 (594 mg, 91%

yield).

¹

H NMR (300 MHz, CDCl

3

) δ 7.29–7.18 (m, 2H), 6.96 (s, 1H), 6.88–6.80 (m, 2H), 6.71 (s, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.76 (s, 3H), 2.98 (t, J = 8.2, 2H), 2.63 (t, J = 8.2, 2H).

dimethyl 2-(trimethylsilyl)cycloprop-2-ene-1,1-dicarboxylate (274):

Prepared by an improved procedure based on that reported by Gevorgyan and coworkers.

⁵

To a flame-dried round-bottom flask equipped with a magnetic stir bar was added bis[rhodium(α,α,α’,α’-tetramethyl-1,3-benzenedipropionic acid)] (0.7 mg, 0.9 µmol, 0.016 mol %) and trimethylsilylacetylene (272, 0.82 mL, 5.75 mmol, 1 equiv).

The flask was sealed with a rubber septum, then evacuated and backfilled with argon three times. Dichloromethane was then added (10 mL, 0.6 M) and the flask was cooled in an ice-water bath with stirring. Diazodimethylmalonate (0.9982 g, 6.3 mmol, 1.1 equiv) was added dropwise, then the flask was removed from the bath and allowed to

TMS

CO₂Me N2

MeO₂C

Rh₂(esp)₂ (cat.) CH2Cl2, 0→23 °C

TMS CO₂Me MeO₂C

273

THF, H₂O, 0 °C K2CO3

CO₂Me MeO₂C

274 272

starting material was observed (TLC), and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (20:1 → 6:1 hexanes:EtOAc) to afford cyclopropene 273 as a blue oil which was carried forward directly to the next stage. Cyclopropene 273 was dissolved in tetrahydrofuran (30 mL) in a round-bottom flask, and the solution was cooled in an ice-water bath. To this solution was added K

2

CO

3

(10 mL, 10% in water) with stirring. After 10 minutes, TLC indicated complete consumption of starting material (R

f

: 3:1 hexanes:EtOAc, SM = 0.62, prod = 0.21). The phases were separated and the organic phase was concentrated to an approximate volume of 5 mL. The aqueous and organic phases were recombined and diluted with water (10 mL) and diethyl ether (25 mL). The phases were separated and the aqueous layer was extracted with additional diethyl ether (25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (9:1 hexanes:EtOAc) to afford cyclopropene 274 (634.1 mg, 70% yield) as an amorphous white solid. The characterization data matched those reported by Gevorgyan and coworkers.

⁵

dimethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1,1- dicarboxylate (248):

In a nitrogen filled glove-box, an oven-dried scintillation vial was charged with bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (5.2 mg, 0.013 mmol, 0.02 equiv)

CO2Me MeO₂C

274

HBpin (1.1 equiv) [Rh(COD)₂]BF₄ dppb, CH2Cl2, 23 °C

CO2Me MeO₂C

248 Bpin

dichloromethane, affording an orange solution. A separate one dram vial was charged with cyclopropene 274 (99.5 mg, 0.64 mmol, 1 equiv) and pinacolborane (100 μL, 0.7 mmol, 1.1 equiv). The mixture was dissolved in dichloromethane (0.5 mL) and transferred into the first vial; the second vial was then washed with additional dichloromethane (0.3 mL) and transferred into the first vial. The reaction was stirred for 17 hours and complete conversion of the starting material was observed (TLC: 3:1 hexanes:EtOAc, R

f

: SM = 0.21, product: 0.46). The reaction mixture was dry-loaded onto SiO

2

(~1 mL) and purified by silica gel column chromatography (8:1 hexanes:EtOAc) to afford cyclopropane 248 (160.7 mg, 89% yield). The characterization data matched those reported by Gevorgyan.

⁵

dimethyl 2-(tributylstannyl)cyclopropane-1,1-dicarboxylate (249):

Prepared by a procedure reported by Gevorgyan and coworkers.

⁶

In a nitrogen filled glove-box, an oven-dried scintillation vial was charged with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.002 mmol). The vial was capped with a screw cap fitted with a Teflon septum and removed from the glovebox. THF (1.55 mL) was added and the mixture was stirred until the catalyst dissolved. The solution was then cooled to –78 °C under nitrogen and tributyltin hydride (460 μL, 0.34 mmol) was added. Finally, a solution of the starting material (274, 250 mg, 0.31 mmol) in THF (0.5 mL) was added and the reaction was stirred at –78 °C for five minutes. Upon completion

CO₂Me MeO₂C

274

Bu₃SnH (1.1 equiv) Pd(Ph₃P)₄ THF, –78 °C

CO₂Me MeO₂C

249 SnBu3

column chromatography (hexanes) to afford cyclopropylstannane 249 (510 mg, 72%

yield). The characterization data match those reported by Gevorgyan.

⁶

dimethyl 2-(3,4-dimethoxyphenyl)cyclopropane-1,1-dicarboxylate (252):

Cyclopropane 252 was synthesized following our standard procedures. See General Proceedures A and B, Experimental Section, Chapter 2. The characterization data match those reported by Müller.

²⁰

dimethyl 2-(furan-3-yl)cyclopropane-1,1-dicarboxylate (261)

Cyclopropane 261 was synthesized following our standard procedures. See General Proceedures A and B, Experimental Section, Chapter 2. The characterization data match those reported by Skvorcova.

²¹

dimethyl 2-(3,4,5-trimethoxyphenyl)cyclopropane-1,1-dicarboxylate (264):

MeO

MeO

CHO MeO₂C CO₂Me piperidine (0.1 equiv)

AcOH (0.1 equiv) PhH, Dean–Stark

MeO

MeO

CO₂Me CO₂Me

Me S Me O

Me I (1.2 equiv) NaH (1.2 equiv)

DMF, 22 °C

MeO

MeO

CO₂Me MeO₂C

276 252

275

CHO MeO2C CO2Me piperidine (0.1 equiv)

AcOH (0.1 equiv) PhH, Dean-Stark

CO₂Me CO₂Me

(1.2 equiv) NaH (1.2 equiv)

DMF, 22 °C

CO₂Me MeO₂C

278 261

O O

O

277

Me S Me O

Me I

MeO

MeO

CHO MeO₂C CO₂Me piperidine (0.1 equiv)

AcOH (0.1 equiv) PhH, Dean-Stark

MeO

MeO

CO₂Me CO₂Me

(1.2 equiv) NaH (1.2 equiv)

DMF, 22 °C

MeO

MeO

CO₂Me MeO₂C

280 264

OMe OMe

OMe 279

Me S Me O

Me I

Proceedures A and B, Experimental Section, Chapter 2. The characterization data match

those reported by Melnikov.

⁷