Experimental Methods and Analytical Data

Iminothiazolidines (S)-525 and (S)-552 are extremely versatile heterocycles

6.14 Experimental Methods and Analytical Data

6.14.1 Materials and Methods

Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried or oven-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents (distilled or passed over a column of activated alumina).

³⁵

Commercially obtained reagents were used as received with the exception of tetra(n- butyl)ammonium bromide (TBAB), zinc(II) chloride, zinc(II) bromide, zinc(II) iodide, zinc(II) triflate, tin(II) triflate, lithium bromide, tetrakis(acetonitrile)copper(I) hexafluorophosphate, and tetrakis(triphenylphosphine)palladium(0), which were stored in a nitrogen-filled glovebox. Et

3

N and pyridine were distilled from calcium hydride immediately prior to use. Methanol was distilled from magnesium methoxide immediately prior to use. Iodosobenzene

³⁶

and diphenylcarbodiimide

³⁷

were prepared by known methods. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-LCMS. TLC was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, or p-anisaldehyde staining.

SiliaFlash P60 Academic Silica gel (particle size 0.040-0.063 mm) was used for flash

chromatography.

¹

H and

¹³

C NMR spectra were recorded on a Varian Inova 500

spectrometer (500 MHz and 126 MHz, respectively) and are reported in terms of

chemical shift relative to residual CHCl

3

( δ 7.26 and δ 77.16 ppm, respectively),

D

3

CS(O)CHD

2

( δ 2.50 and δ 39.52 ppm, respectively), or CHDCl

2

( δ 5.32 and δ 53.84

ppm, respectively). Data for

¹

H NMR spectra are reported as follows: chemical shift (δ

ppm) (multiplicity, coupling constant (Hz), integration). Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = complex multiplet, bs = broad singlet. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm

^–1

). High-resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer with fast atom bombardment (FAB+) ionization mode or were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in atmospheric pressure chemical ionization (APCI+), electrospray ionization (ESI+), or mixed (MultiMode: ESI-APCI) ionization mode.

Optical rotations were measured on a JASCO P-2000 polarimeter using a 100 mm path length cell at 589 nm. Analytical supercritical fluid chromatography (SFC) was performed with a Mettler SFC supercritical CO

2

analytical chromatography system utilizing Chiralpak (AD-H or AS-H) or Chiralcel (OB-H or OD-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd.

6.14.2 General Experimental Procedures

General Procedure A. Direct aziridination of olefins.

³⁸

To a flame-dried round-bottom flask with a stir bar were added p- toluenesulfonamide (5.60 mmol, 1.40 equiv), tetrakis(acetonitrile)copper(I)

R

R N S

O O

CH3

Cu(CH₃CN)₄PF₆ PhIO, 3 Å MS

CH₃CN 0 °C→23°C

S

O O

CH₃

NH₂

469 500

hexafluorophosphate (0.40 mmol, 0.10 equiv), the appropriate olefin (469, 4.00 mmol, 1.00 equiv), activated 3 Å molecular sieves (2.40 g, 600 mg/mmol olefin), and acetonitrile (10 mL). The stirred suspension was cooled to 0 °C (ice/H

2

O bath) at which time iodosobenzene (5.60 mmol, 1.40 equiv) was added as a solid in one portion. The bath was immediately removed and the reaction mixture was allowed to warm to ambient temperature. Upon consumption of starting material (determined by TLC or LCMS analysis, ca. 12–48 h), the mixture was filtered through Celite, washing with acetonitrile (50 mL) and ethyl acetate (50 mL). The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in hexanes eluent).

General Procedure B. Ring closure of amino alcohols.

³⁹

A flame-dried round-bottom flask with a stir bar was charged with 2-phenylglycinol (553, 0.73 mmol, 1.00 equiv), which was then suspended in CH

2

Cl

2

(500 µL) and pyridine (250 µL). The stirred suspension was cooled to 0 °C (ice/H

2

O bath) at which time the appropriate sulfonyl chloride (2.19 mmol, 3.00 equiv) was added in one portion.

The bath was immediately removed and the reaction mixture was allowed to warm to ambient temperature. Upon completion (determined by TLC or LCMS analysis, ca. 1–5 h), the mixture was diluted with CH

2

Cl

2

(12 mL), and washed with aqueous 2 N HCl (3 x 4 mL). The combined acidic aqueous layers were extracted with CH

2

Cl

2

(1 x 4 mL).

The organic layers were combined and carefully washed with aqueous 2 N KOH (6 x 8

N S

O O

R

553 NH₂

OH

Cl S

O O

R

pyridine CH₂Cl₂ 0 °C→23 °C

520

mL). The combined basic aqueous layers were then extracted with CH

2

Cl

2

(1 x 12 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EtOAc in hexanes eluent).

General Procedure C. Isothiocyanate (3 + 2) cycloaddition with 2-subsituted aziridines.

To an oven-dried 1-dram vial equipped with a magnetic stir bar was added zinc(II) bromide (113 mg, 0.50 mmol, 1.25 equiv), freshly powdered with a mortar and pestle, 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 an inert atmosphere. To a separate, oven-dried 1-dram vial was added the appropriate aziridine (554, 0.40 mmol, 1.00 equiv). The vial was sealed with a screw cap fitted with a Teflon septum and anhydrous CH

2

Cl

2

(0.60 mL) and isothiocyanate (0.80 mmol, 2.00 equiv) were added.

The mixture was transferred to the first vial with a rinse of anhydrous CH

2

Cl

2

(0.20 mL).

The heterogeneous reaction mixture was then allowed to stir at ambient temperature.

Upon consumption of the aziridine (determined by TLC or LCMS analysis), the reaction solution was diluted with CH

2

Cl

2

(3 mL) and CH

3

OH (1 mL), adsorbed onto Celite, and purified by silica gel column chromatography (acetone in hexanes eluent).

R¹ N R²

(2.00 equiv) ZnBr₂ (1.25 equiv)

CH₂Cl₂, 23 °C

S N

R¹ R³N

R² R³-N • S

554 555

General Procedure D. Carbodiimide (3 + 2) cycloaddition with 2-subsituted aziridines.

To an oven-dried 1-dram vial equipped with a magnetic stir bar was added zinc(II) bromide (113 mg, 0.50 mmol, 1.25 equiv), freshly powdered with a mortar and pestle, 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 an inert atmosphere. To a separate, oven-dried 1-dram vial was added the appropriate aziridine (554, 0.40 mmol, 1.00 equiv). The vial was sealed with a screw cap fitted with a Teflon septum and anhydrous CH

2

Cl

2

(0.60 mL) and carbodiimide (0.41 mmol, 1.02 equiv) were added. The mixture was transferred to the first vial with a rinse of anhydrous CH

2

Cl

2

(0.20 mL). The heterogeneous reaction mixture was then allowed to stir at ambient temperature. Upon consumption of the aziridine (determined by TLC or LCMS analysis), the reaction solution was diluted with CH

2

Cl

2

(3 mL) and CH

3

OH (1 mL), adsorbed onto Celite, and purified by silica gel column chromatography (acetone in hexanes or CH

3

OH in CH

2

Cl

2

eluent).

General Procedure E. Stereoselective Isothiocyanate (3 + 2) cycloaddition with 2- subsituted aziridines.

To an oven-dried 1-dram vial equipped with a magnetic stir bar was added powdered zinc(II) chloride (68 mg, 0.50 mmol, 1.25 equiv) in an inert atmosphere

R¹ N R²

(1.02 equiv) ZnBr₂ (1.25 equiv)

CH₂Cl₂, 23 °C

N N

R¹ R³N

R² R³-N • N-R³

R³

554 556

R¹ N R²

(10.0 equiv) ZnCl₂ (1.25 equiv)

CH₂Cl₂, 23 °C

S N

R¹ R³N

R² R³-N • S

(R)-554 (S)-555

glovebox. The vial was sealed with a screw cap fitted with a Teflon septum, removed from the glovebox, and placed under an inert atmosphere. To a separate, oven-dried 1- dram vial was added the appropriate aziridine ((R)-554, 0.40 mmol, 1.00 equiv). The vial was sealed with a screw cap fitted with a Teflon septum and anhydrous CH

2

Cl

2

(0.60 mL) and isothiocyanate (4.00 mmol, 10.0 equiv) were added. The mixture was transferred to the first vial with a rinse of anhydrous CH

2

Cl

2

(0.20 mL). The heterogeneous reaction mixture was then allowed to stir at ambient temperature. Upon consumption of the aziridine (determined by TLC or LCMS analysis), the reaction solution was diluted with CH

2

Cl

2

(3 mL) and CH

3

OH (1 mL), adsorbed onto Celite, and purified by silica gel column chromatography (acetone in hexanes).

6.14.3 Aziridine Synthesis and Characterization Data