KBS17-5 - Propargylation of 1,6-diaminohexane

[KlementineJBS]

Link to HIRAC, original method and master page.

Last attempt is #22.

KBS17 Generic propargylation of 1,n-diamine.docx

Reaction scheme

Outcome

20 mg (0.0510 mmol), 10%

Overall, it does not seem to be worth attempting to "re-react" the mono product to obtain more of the bis product, as the yield was so poor. In future, the reaction will simply be uspcaled, though optimisation of solvents etc will still be attempted.

[KlementineJBS]

25.07.22

1. Added NaH (210 mg, 8.75 mmol) to a dry flask under nitrogen
2. Added mono-propargyl 1,6-diaminohexane (SP of KBS17, 175 mg, 0.494 mmol) by solution transfer (dry DMF, 8 mL)
3. Added 0.06 mL propargyl bromide (0.633 mmol, 1.3 equiv.)
4. Left stirring from 4 pm

[KlementineJBS]

26.07.22

Reaction had turned black overnight.

[KlementineJBS]

28.07.22

5. Diluted reaction with NH4Cl (10 mL) and water (40 mL).
6. Extracted with toluene (4 x 25 mL)
7. Washed with H2O (5 x 75 mL)
8. Washed with brine (100 mL)
9. Dried over MgSO4 and rotovapped

NMR

Product appears to still be a combination of mono/bis propargylated hexadiamine. Probably need to column manually to determine percentage yield.

KBS17-5 cr_1.zip

KBS17-5 cr processed.pdf

[KlementineJBS]

29/07/22

Peaks at both 377.24 [M+Na] (mono product) and 415.26 [M+Na] (bis product).

KBS17-5 cr.d.zip
KBS17-5 cr.pdf

[KlementineJBS]

03.08.22

Performed a manual column to isolate mono and bis products. Used ~ 10 cm silica (possibly too much) and accidentally disturbed column bed part of the way through, possibly disrupting flow.

Column conditions:
50 mL 5:95 EtOAc/pet benzine
75 mL 6.7:93.3 EtOAc/pet benzine
100 mL 10:90 EtOAc/pet benzine
200 mL 20:80 EtOAc/pet benzine
50 mL 30:70 EtOAc/pet benzine

TLC's indicated bis product in fractions 18, 19, 20 and 22, 23, 24. Mono product appeared to be in fractions 26 - 35 but some SM was evident from fraction 29 onwards.

Note that M and D refer to references standards of mono-substituted and double-substituted products respectively, obtained from Nick Smith

[KlementineJBS]

03.08.22

Collected fractions 18 - 20 and 22 - 24 (believed to be bis product).

Empty vial: 16.1803
Full vial: 16.2002 g
Mass: 19.9 mg

H NMR

1H NMR (300 MHz, CDCl3) δ 4.02 (4H), 3.30 (4H), 2.18 (2H), 1.54 (4H), 1.47 (18H), 1.31 (4H).

Mysterious peak at 9.16 - seems like solvent (clean singlet, integrates to 0.43). There also appears to be water in the sample resulting in an increased integral at 1.54 (should be 4H but shows up as ~ 7H).

KBS17-5 F18-24_1.zip

KBS17-5 F18-24 processed.pdf

During the column, very faint signs of product could be seen in some fractions before F18. These weren't collected as the signal was so faint, however, collecting them may increase yield.