GENERAL AND MISCELLANEOUS EXPERIMENTAL PROCEDURES

COPE REARRANGEMENT

2.8 EXPERIMENTAL SECTION

2.8.2 GENERAL AND MISCELLANEOUS EXPERIMENTAL PROCEDURES

General Procedure A. Knoevenagel condensation.

A round-bottom flask was charged with the appropriate aldehyde (181, 14.4 mmol), followed by benzene (85 mL), dimethyl malonate (15.8 mmol), piperidine (1.44 mmol), and acetic acid (1.44 mmol). The flask was equipped with a Dean-Stark trap and condenser and the solution heated to reflux. Upon completion (as determined by TLC analysis), evaporation of the solvent gave the crude product, which was purified by silica gel column chromatography.

General Procedure B. Corey–Chaykovsky cyclopropanation.

Sodium hydride (2.56 mmol, 60% dispersion in mineral oil) was suspended in anhydrous DMF (4 mL) in a flame-dried round-bottom flask under nitrogen.

Trimethylsulfoxonium iodide (2.56 mmol) was added, and the solution stirred at ambient temperature for 1 hour. A solution of the appropriate benzylidene malonate (182, 2.13 mmol) in anhydrous DMF (2 mL) was added, and the reaction mixture allowed to stir at room temperature. Upon completion (as determined by TLC analysis), the solution was poured onto a mixture of ice and aqueous 2 M HCl (10 mL) and extracted with diethyl ether (3 x 30 mL). The combined organic layers were washed once with brine, dried over

R CO₂Me CO₂Me R

O H

CO₂Me MeO₂C

piperidine (0.1 equiv) AcOH (0.1 equiv) PhH, Dean-Stark

181 182

R CO₂Me CO₂Me Me S

Me O

Me (1.2 equiv) NaH (1.2 equiv)

DMF, 22 °C

182 ^R 131

CO₂Me CO₂Me I

magnesium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography.

General Procedure C. Styrene cyclopropanation.

Rh

₂

(esp)

₂

(0.3 mg) was added to a flame-dried round-bottom flask, which was then evacuated and backfilled with nitrogen three times. The appropriate styrene (183, 5.0 mmol) and anhydrous dichloromethane (5 mL) were then added and the solution was stirred under nitrogen and cooled in an ice bath. A solution of diazodimethylmalonate (6.0 mmol) in anhydrous dichloromethane (5 mL) was added dropwise over 20 minutes.

The reaction solution was then allowed to warm to ambient temperature. Upon completion (as determined by TLC analysis), the crude product was adsorbed onto silica gel and purified by column chromatography. When traces of the rhodium catalyst remained after chromatography (as determined by a blue discoloration), the product was dissolved in anhydrous benzene (1.5 mL) in a flame-dried round-bottom flask. A solution of tetrakis(hydroxymethyl)phosphonium hydroxide (10 mL, 1 M in isopropanol) was added,

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and the mixture was stirred at 60 °C for 12 hours. The solution was then cooled to room temperature, diluted with diethyl ether (20 mL), washed once with water and once with brine, dried over magnesium sulfate, filtered, and concentrated to give the purified product.

R

CO₂Me MeO₂C

N₂ (1.2 equiv) Rh(esp)₂ (cat.) CH₂Cl₂, 0 °C → 22 °C

183 ^R 131

CO₂Me CO₂Me

General Procedure D. Isocyanate (3 + 2) reaction with D-A cyclopropanes, Method A.

To a flame-dried 10 mL flask equipped with a magnetic stir bar was added iron(III) chloride (0.44 mmol) in an inert atmosphere glovebox. The flask was sealed with a Teflon septum, removed from the glovebox, and placed under a nitrogen atmosphere. To an oven-dried 1 dram vial were added the appropriate cyclopropane (131, 0.4 mmol) and isocyanate (1.2 mmol). The vial was sealed with a screw cap fitted with a Teflon septum, and this mixture was transferred to the reaction flask as a solution in anhydrous dichloromethane (1 mL + 0.33 mL rinse). The solution was then allowed to stir at ambient temperature under nitrogen. Upon consumption of the cyclopropane (as determined by TLC analysis), the reaction solution was diluted with dichloromethane, adsorbed onto Celite, and purified by silica gel column chromatography.

General Procedure E. Isocyanate (3 + 2) reaction with D-A cyclopropanes, Method B.

To an oven-dried 1 dram vial equipped with a magnetic stir bar was added iron (III) chloride (0.44 mmol) and oven-dried 4Å molecular sieves (50 mg). The vial was sealed with a screw cap fitted with a rubber septum, and was placed under a nitrogen atmosphere. To a second oven-dried 1 dram vial was added the appropriate cyclopropane (131, 0.4 mmol) and isocyanate (1.2 mmol). The vial was sealed with a screw cap fitted with a Teflon septum and this mixture was transferred to the first vial as a solution in anhydrous dichloromethane (1 mL + 0.33 mL rinse). The mixture was then allowed to stir at ambient temperature under nitrogen. Upon consumption of the cyclopropane (as

FeCl3 (1.1 equiv) CH₂Cl₂ , 23°C CO2Me

CO2Me

R¹

N R¹

O R²

CO₂Me CO₂Me

131 135

R²–NCO (3.0 equiv)

determined by TLC analysis), the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was washed twice with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography.

General Procedure F. Isothiocyanate (3 + 2) reaction with D-A cyclopropanes.

To an oven-dried 1 dram vial equipped with a magnetic stir bar was added tin(II) trifluoromethanesulfonate (0.44 mmol) in an inert atmosphere glovebox. The vial was sealed with a screw cap fitted with a Teflon

^®

septum, removed from the glovebox, and placed under a nitrogen atmosphere. To a separate, oven-dried 1 dram vial were added the appropriate cyclopropane (131, 0.4 mmol) and isothiocyanate (0.8 mmol). The vial was sealed with a screw cap fitted with a Teflon

^®

septum, and the mixture was transferred to the first vial as a solution in anhydrous dichloromethane (1 mL + 0.33 mL rinse). The heterogeneous reaction mixture was then allowed to stir at ambient temperature under nitrogen. Upon consumption of the cyclopropane (as determined by TLC analysis), the reaction solution was diluted with dichloromethane (3 mL) and methanol (1 mL), adsorbed onto Celite, and purified by silica gel column chromatography. The products of this reaction were often found to be unstable during prolonged storage (~1 week) at ambient temperature; the decomposition products have not been identified.

Sn(OTf)₂ (1.1 equiv) CH₂Cl₂ , 23°C CO₂Me

CO₂Me

R¹

S R¹

N

CO2Me CO2Me

131 156

R²–NCS (2.0 equiv)

R²

General Procedure G. Carbodiimide (3 + 2) reaction with D-A cyclopropanes.

To an oven-dried 1 dram vial equipped with a magnetic stir bar was added tin(II) trifluoromethanesulfonate (0.44 mmol) in an inert atmosphere glovebox. The vial was sealed with a screw cap fitted with a Teflon

^®

septum, removed from the glovebox and placed under a nitrogen atmosphere. To a separate, oven-dried 1 dram vial were added the appropriate cyclopropane (131, 0.4 mmol) and carbodiimide (0.44 mmol). The vial was sealed with a screw cap fitted with a Teflon

^®

septum, and the mixture was transferred to the first vial as a solution in anhydrous dichloromethane (1 mL + 0.33 mL rinse). The heterogeneous reaction mixture was then allowed to stir at ambient temperature under nitrogen. Upon consumption of the cyclopropane (as determined by TLC analysis), the reaction solution was diluted with dichloromethane (3 mL) and methanol (1 mL), adsorbed onto Celite, and purified by silica gel column chromatography. The product obtained after column chromatography is an amidinium salt, which is dissolved in DCM, and washed with aqueous sodium hydroxide (0.1 M) and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo to yield the free amidine base.

Sn(OTf)₂ (1.1 equiv) CH2Cl2 , 23°C CO₂Me

CO₂Me

R¹

N R¹

N

CO₂Me CO₂Me

131 169

R²–NCN–R² (1.1 equiv) R² R²

CO₂Me CO₂Me

MeO

140

MeO

143 MeO₂C

CO₂Me

Sn(OTf)₂ (20 mol %) CHCl₃, 19 °C

Preparation of Styrene 143.

A 1 dram vial, equipped with a magnetic stir bar, was charged with tin(II) triflate

(16.7 mg, 0.04 mmol, 0.2 equiv), then cyclopropane 140 (54.1 mg, 0.2 mmol, 1 equiv)

was added as a solution in chloroform (1 mL). Stirring was initiated and a heterogeneous

mixture with a yellow supernatant resulted. Consumption of starting material was

observed by LCMS after 35 minutes. The reaction mixture was dry-loaded onto SiO

2

(~1

mL) and purified by silica gel column chromatography (3:1 hexanes:EtOAc) to afford

styrene 143 as a colorless solid. Characterization data match those reported in the

literature.

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