KBS17-9 - Propargylation of 1,6-diaminohexane

[KlementineJBS]

Link to HIRAC, original method and master page.

Last attempt is #33.

KBS17 Generic propargylation of 1,n-diamine.docx

Reaction Scheme

Changes to make

• Will try using DMF dried over molecular sieves
• pass propargyl bromide through an alumina plug
• wash NaH to remove mineral oil

[KlementineJBS]

03.11.22

1. Added NaH (175.3 mg, 4.38 mmol, 3.5 equiv.) to a oven dry flask under nitrogen
2. Washed mineral oil off with pet. benz. (3 x 5 mL)
3. Added KBS3 (397.8 mg, 1.26 mmol) dissolved in DMF dried over sieves (10 mL)
4. left stirring at rt for 1 hr 45 mins

TLC indicated deprotonation step was not complete

Checked again after 2.5 hours. TLC indicated deprotonation was more progressed.

5. Cooled to 0 C
6. Added dropwise propargyl bromide (0.5 mL, 4.67 mmol, 3.7 equiv.) that had been freshly passed through aluminum to remove impurities (e.g. HBr)
7. Left to warm to rt in ice bath overnight

[KlementineJBS]

07.11.22

INSERT TLC

8. Quenched with 20 mL NH4Cl (10-15 minutes stirring)
9. Extracted with toluene (5 x 25 mL) and washed with water (5 x 50 mL)
10. Washed with brine (100 mL) and dried over mag sulphate
11. Filtered and rotovapped

Empty vial: 15.6536
Full vial: 16.0547
Mass: 401.1

H NMR

KBS17-9_1.zip
KBS17-9 cr processed.pdf

Evidence of both mono and bis products.

LCMS/MS

KBS-17-9_1-D_5_1_392.d.zip
KBS-17-9_1-D_5_1_392__Generic_Display_Report.pdf
KBS-17-9_1-D_5_1_392_Compound_Spectrum_List_Report.pdf

[KlementineJBS]

15.11.22 - columning crude product

10 cm silica

Ran ~ 200 mL of 5% ethyl acetate before disturbing column bed irreparably. Salvaged as much crude product as possible.

Salvaged product = 379.5 mg

Note that column numbering was continued across the two columns i.e. fraction 10 is the last collected before the column was ruined and fraction 11 is the first collected from the fresh column.

Second column

• 200 mL 5% ethyl acetate in petroleum benzine

• 250 mL 10%

• 200 mL 20%

• 50 mL 30%

• 200 mL 100%

[KlementineJBS]

16.11.22 - Results of column

Compound	Fractions	Tare weight	Final weight	Mass	Percentage yield (see notes)
Bis	39-44	15.7929	15.8686	75.7 mg (0.192 mmol)	15%
Bis/mono	45-46	15.7705	15.7783	17.8 mg (0.045 mmol)	4%
Mono	47-51	15.7911	15.9331	142 mg (0.400 mmol)	32%
Mono/SM	52-54	15.8134	15.8173	4 mg (0.00113 mmol)	< 1%
SM	55+	15.8383	15.9395	101.2 mg, 0.320 mmol)	25%

H NMR

KBS17-9 F39-44_1.zip - bis product
KBS17-9 45-46_1.zip - mixed bis/mono
KBS17-9 F47-51_1.zip - mono product
KBS17-9 55+_1.zip - starting material

KBS17-9 column fractions.pdf

[KlementineJBS]

21.11.22

LRMS

KBS17-9 pure compounds.d.zip

KBS17-9 39-44.pdf
Bis product - 415.26 [M+Na]+

KBS17-9 47-51.pdf
Mono product - 377.23 [M+Na]+

KBS17-9 55+.pdf
SM - 339.23 [M+Na]+

[KlementineJBS]

22.11.22

Decided to run 20% MeOH in DCM through column to get rid of last band - see image.