KBS50-2 - Nosyl protection of bis(3-aminopropyl)amine

[KlementineJBS]

Link to HIRAC and master page #157

KBS43 - Nosyl protection of linear diamine .docx

Reaction scheme

Outcome

2.6531 g (3.86 mmol, 88%)

[KlementineJBS]

19.03.24

1. Added SM amine (577.8 g, 4.40 mmol) to a flask
2. Added DCM (10 mL)
3. Added triethlyamine (3.0 mL, 21.78 mmol, 5.0 equiv.)
4. Cooled to 0 C
5. Added nosyl chloride (3.2284 g, 14.6 mmol, 3.3 equiv.)

Stirred at rt from ~ 11.15 am.

TLC analysis has been difficult. TLCs below were taken at ~12 pm, ~4 pm and ~ 5pm (left to right) and run in 90% MeOH in DCM with 1% ammonium hydroxide, stained with ninhydrin.

Note that in first 2, SM was the amine, but in last one, SM was nosyl chloride. Currently unsure which spots represent which amine - see #187 for some thoughts.

[KlementineJBS]

20.03.24

TLC indicated reaction is still not complete. Heated from 10 am until 3 pm (~32 C) then added triethylamine (1.5 mL) and increased heat to 60 C at 4 pm.

[KlementineJBS]

25.03.24

Final TLC (bottom right) in 5% MeCN/DCM. Shows that reaction has gone to completion one way or another. Not yet sure what that spot actually represents.

Reaction mixture had been left heating at 62 C since Thursday afternoon. RM was thick and black and upon rotovapping was found to have a large quantity of small whiteish crystals - reminiscient of salt - but these were not soluble in water, DCM or ethyl acetate. Solid crystals and black solution were roughly separated and NMR attempted on solid - however, it didn't appear to dissolve so signals may be from residue of black liquid.

[KlementineJBS]

LRMS

Signs of tris-nosyl product only (685.10- [M-H]-, 709.05 [M+Na]+) and some signals assumed to be from byproducts (150.20+, 337.20+).

KBS50-2 cr.d.zip KBS50-2 cr.pdf

[KlementineJBS]

H NMR

Difficult to tell definitively from this.

KBS50-2 cr.pdf KBS50-2 cr solid_1.zip

[KlementineJBS]

26.03.24

Tried washing/triturating with a few different solvents to remove nosyl chloride.

Triturations

General method: added 3 mL solvent and sonicated for 5 minutes. Removed solvent and completed 4 more triturations (3 mL each) before rotovapping.

Petroleum benzine - couldn't see anything dissolving.

Ether - couldn't see anything dissolving.

Methanol - large amount of the tar-like product dissolved.

Washes

Water - dissolved product in DCM and washed (5 x 4 mL), then dried and rotovapped down.

[KlementineJBS]

H NMR

Cleanest result is a simple water wash, followed by methanol. Water seems preferable as methanol dissolves a lot of product. Will attempt a DCM 2-phase workup.

(Note water sample is contaminated with ether.)

KBS50-2 trituration screen.pdf

KBS50 SM_1.zip KBS50-2 wash - water_1.zip KBS50-2 wash - pet benz_1.zip KBS50-2 wash - methanol_1.zip KBS50-2 wash - ether_1.zip

[KlementineJBS]

27.03.24

Performed a two-phase workup with ~150 mL DCM. Washed with water (4 x 80 mL) and brine (80 mL), dried and rotovapped down.

During rotovapping, product goes from a thick black tar (like vegemite) to a light silvery brown foam. Had to split across 2 vials to prevent bumping.

Vial 1: 15.9223 g mass: 1.5734 g

Vial 2: 15.7262 g mass: 506.4 mg

Vial 3: 15.9593 g mass: 573.3 mg

total: 2.6531 g (3.86 mmol, 88%)

[KlementineJBS]

H NMR

Looks mostly clean by NMR - some solvent peaks, especially water.

KBS50-2 cr washed.pdf NEO500-20240327-6 KBS50-2 cr_1.zip