KBS17-10 - 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)
• propargyl bromide was passed through 2cm of neutral alumina)

[KlementineJBS]

29.11.22

1. Added NaH (163.5 mg of 60% dispersion in mineral oil, 4.09 mmol, 2.90 equiv.) to a dry flask
2. Washed with pet. benz. (3 x 5 mL)
3. Added KBS3-3 (447.7 mg, 1.41 mmol) dissolved in dry DMF (10 mL)
4. Left stirring at rt from 10.30 am

TLC indicated "activation step" (deprotonation by NaH) was complete at 1.45 pm.

Reaction at 1.45 pm

5. Cooled to 0 C
6. Added propargyl bromide (0.5 mL, 80% in toluene, 6.60 mmol, 4.7 equiv.)

Reaction went black instantly upon addition of propargyl bromide.

TLC at 4.45 pm indicated formation of mono and bis product already, but SM remained.

[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]

01.12.22

TLC at 10 am.

Decided to work up despite SM remaining (~ 48 hours reaction time).

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

Reaction after quenching

Reaction after brine wash

Empty vial: 15.8697
Full vial: 16.3023
Mass: 432.6 mg

[KlementineJBS]

8.12.22

Column

Ethyl acetate/pet. benz.

100 mL - 5%
250 mL - 10%
200 mL - 20%
100 mL - 50%
100 mL - 100%

Label	Fractions	Vial weight (g)	Vial weight (full)	Mass (mg)	Moles (mmol)	Yield
B	10-12	15.7548	-	-	-	-
C	13-22	15.7553	15.8522	96.9	0.247	18%
D	23-24	15.4883	15.5064	18.1	0.046	3%
E	25-29	15.5235	15.6196	96.1	0.271	19%
F	30-34	15.9494	15.9747	25.3	0.071	5%
G	35+

[KlementineJBS]

07.12.22

Column TLCs.

[KlementineJBS]

20.12.22

LRMS

KBS-17-10_2-A,6_1_693-1.pdf
KBS-17-10_2-A,6_1_693.pdf

Evidence of mono product (377.26) and bis product (415.29) in a ratio of roughly 77:100 i.e. mono = 44%, bis = 56%.