KBS17-11 - Propargylation of 1,6-diaminohexane

[KlementineJBS]

Link to HIRAC, original method and master page.

Last attempt is #45.

KBS17 Generic propargylation of 1,n-diamine.docx

Reaction Scheme

Changes to make

• Using DMF with 100 ppm water (i.e. properly dry - tested on Karl Fischer titrator)
• add 15-crown-ether

[KlementineJBS]

29.11.22

1. NaH (157.1 mg, 60% dispersion in mineral oil, 3.93 mmol)
2. Washed NaH with pet. benz. (3 x 5 mL)
3. Added KBS3-3 (466.9 mg, 1.48 mmol) dissolved in dry DMF (10 mL)
4. Added extra NaH (50.8 mg, 1.27 mmol) -- for a total of 5.20 mmol, 3.51 equiv.
5. Added 15-crown-ether (0.8 mL, 4.04 mmol, 2.73 equiv.)
6. Left stirring at rt from 11.30 am

TLC repeatedly indicated that SM remained. At 4.30 pm, TLC was unclear but seems to have little SM remaining.

7. Cooled to 0 C
8. Added propargyl bromide (0.5 mL, 80% in toluene, 6.60 mmol, 4.7 equiv.) dropwise
9. Left stirring at rt from 4.45 pm

[KlementineJBS]

30.11.22

TLC at 9.30 am indicated formation of mono and bis products.

20% ethyl acetate/pet. benz.; from left to right: 17-10, 17-10/starting material co spot, starting material, 17-11/starting material cospot, 17-11

[KlementineJBS]

30.11.22

TLC at 5 pm.

Cooled to 0 C and added extra propargyl bromide (0.3 mL, 3.19 mmol, 2.2 equiv.)

[KlementineJBS]

01.12.22

TLC at 1.30 pm.

  30% ethyl acetate in pet. benz.

Decided to work up anyway for better comparison with #50.

11. Quenched with NH4Cl (20 mL)
12. Extracted with toluene (4 x 50 mL)
13. Washed with water (5 x 100 mL)
14. Washed with brine (125 mL)
15. Dried over mag sulphate and rotovapped.

Reaction immediately after quenching

First extraction - much darker in colour than #50

After brine wash

Empty vial: 15.6260 Full vial: 16.1310 Mass: 505 mg

[KlementineJBS]

20.12.22

LRMS

KBS-17-11_2-A,7_1_694.pdf

Evidence of SM (339.22), mono product (377.23) and bis product (415.25) in a ratio of roughly 10:7:6 i.e. SM = 43%, mono = 30%, bis = 26%.

[KlementineJBS]

13.12.22

Column TLCs.