General and Miscellaneous Experimental Procedures

R CO2Me CO2Me R O H CO2Me MeO2C piperidine (0.1 equiv) AcOH (0.1 equiv) PhH, Dean-Stark

General Procedure A. Knoevenagel condensation.

A round-bottom flask was charged with the appropriate aldehyde (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.

R CO2Me CO2Me R CO2Me CO2Me Me S Me O Me I– (1.2 equiv) NaH (1.2 equiv) DMF, 22 °C

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 (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 2 M HCl(aq) (10 mL) and extracted with diethyl ether (3 x 30

mL). The combined organic layers were washed once with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography.

R R CO2Me CO2Me CO2Me MeO2C N2 (1.2 equiv) Rh(esp)2 (cat.) CH2Cl2, 0 °C ! 22 °C 82

General Procedure C. Styrene cyclopropanation.

Rh(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 (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 (82) (6.0 mmol) in anhydrous dichloromethane (5 mL) was added dropwise over 20 minutes.22

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 µL, 1M in isopropanol) was added,23

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 _CO 2Me CO2Me R'-NCO (3 equiv) FeCl3 (1.1 equiv) CH2Cl2, 22 °C N O CO2Me CO2Me R R'

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

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 (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.

To an oven-dried 1 dram vial equipped with a magnetic stir bar was added iron (III) chloride (0.44 mmol) and oven-dried 4 Å 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 (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 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 column chromatography.

R CO2Me CO2Me R'-NCS (2 equiv) Sn(OTf)2 (1.1 equiv) CH2Cl2, 22 °C S N R' CO2Me CO2Me R

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 (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.

R CO2Me CO2Me R'-N=C=N-R' (1.1 equiv) Sn(OTf)2 (1.1 equiv) CH2Cl2, 22 °C R'N N CO2Me CO2Me R R'

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 (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.

Ph NCS i-PrNH2 (2 equiv) THF, 23 °C ! reflux N_H N_H S i-Pr Ph MsCl (2 equiv) Et3N (3 equiv) DMAP (0.04 equiv) CH2Cl2 PhN C Ni-Pr 83 77

Thiourea 83. Prepared according to the method of Zhou and coworkers.24

To a flame-dried round-bottom flask, equipped with a magnetic stir bar and fitted with a

rubber septum was added phenyl isothiocyanate (1.2 mL, 10 mmol, 1 equiv) and anhydrous THF (32 mL) under an inert atmosphere. To the stirring solution was added isopropylamine (1.64 mL, 20 mmol, 2 equiv) dropwise. The rubber septum was quickly replaced with a reflux condenser fitted with a hose adapter, connected to an inert atmosphere manifold. The resulting solution was heated to reflux with stirring for 40 min. The reaction mixture was then cooled to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (60 mL) and washed with aqueous hydrochloric acid (10 mL, 1 N) and brine (10 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude thiourea 82

(1.89 g, 97%) as a white solid which was carried forward directly to the next step in the synthesis.

Carbodiimide 77. Prepared according to the method of Fell and Coppola.25

To a flame-dried, round-bottom flask, equipped with a magnetic stir bar was added crude thiourea 82 (971 mg, 5 mmol, 1 equiv). The flask was sealed with a rubber septum and placed under an inert atmosphere. To the flask was added dry dichloromethane (50 mL, 0.1 M) and freshly distilled triethylamine (2.1 mL, 15 mmol, 3 equiv), followed by a dropwise addition of mesyl chloride (0.78 mL, 10 mmol, 2 equiv). Complete consumption of starting material was observed within 5 minutes, as determined by TLC. The volatiles were removed in vacuo, and a precipitate was observed. The mixture was filtered twice through SiO2 (100 mL), eluting with dichloromethane, then purified by

column chromatography on SiO2 (10:1 hexanes:EtOAc) to afford carbodiimide 77 (332.2

mg, 41% yield) as a yellow oil: Rf = 0.81 (3:1 Hexanes:EtOAc eluent); 1

H NMR (300 MHz, CDCl3) δ 7.38–7.20 (m, 2H), 7.21–7.02 (m, 3H), 3.80 (hept, J = 6.4 Hz, 1H), 1.35

(d, J = 6.5 Hz, 6H); 13

C NMR (75 MHz, CDCl3) δ 140.9, 136.6, 129.4, 124.7, 123.4, 50.3,

24.9; IR (Neat Film, NaCl) 3419, 3067, 2973, 2129, 1637, 1592, 1501, 1454, 1367, 1320 cm-1

; HRMS (ESI) m/z calc’d for C10H13N2 [M+H] + : 161.1073, found 161.1077. MeO CO2Me CO2Me 30 CO2Me CO2Me 27 Sn(OTf)2 (0.2 equiv) CHCl3, 19 °C MeO

Styrene 30. 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 27 (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 SiO2 (~1 mL) and purified by column chromatography on SiO2 (3:1 hexanes:EtOAc)

to afford styrene 30 as a colorless solid: 1

H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.7

Hz, 2H), 6.85 (d, J = 7.7 Hz, 2H), 6.52 (d, J = 16.0 Hz, 1H), 6.31–6.21 (m, 1H), 4.19 (d, J = 8.9 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 9H); 13

C NMR (126 MHz, CDCl3) δ 168.7, 159.7,

134.9, 128.9, 128.0, 118.4, 114.1, 55.8, 55.4, 53.0; IR (NaCl/film) 3002, 2953, 2834, 1736, 1607, 1513, 1251, 1177, 1029 cm-1_{; HRMS (MM: ESI-APCI) m/z calc’d for}

C14H16O5 [M+H] +

: 265.1071, found 265.1076.