KBS17-4 - Propargylation of 1,6-diaminohexane

[KlementineJBS]

Link to HIRAC, original method and master page.

Last attempt is #19.

Next attempt is #23

KBS17 Generic propargylation of 1,n-diamine.docx

Reaction Scheme

Using 1:5 mixture of DMF:THF as solvent.

Outcome

62% overall

Mono product: 164 mg (0.462 mmol), 36% Bis product: 129 mg (0.330 mmol), 26%

[KlementineJBS]

21.07.22

1. Added NaH (449 mg, 11.2 mmol, 8.7 equiv.) to a dry 100 mL flask under nitrogen
2. Added KBS3 (407 mg, 1.29 mmol) by solution transfer (3 mL dry DMF, 15 mL dry THF)
3. After 5 minutes stirring, added propargyl bromide (80% in toluene, 0.5 mL, 4.67 mmol, 3.6 equiv.)
4. Left stirring from 2.15 pm

TLC at 4 pm indicated reaction was not yet complete. (20:80 ethyl acetate:pet benzine)

[KlementineJBS]

22.07.22

Mixture had gone black overnight - this seems to indicate that reaction is occurring.

TLC at 10 am indicated reaction still not complete. Using 30:70 ethyl acetate: pet benzine gives better resolution of spots.

Took off at 4 pm. Diluted with NH4Cl (25 mL) and water (55 mL) then extracted with toluene (4 x 50 mL), washed with water (3 x 125 mL) and brine (150 mL). Dried over MgSO4.

[KlementineJBS]

25.07.22

Rotovapped down organic phase.

Empty vial: 16.0488 g Full vial: 16.6544 g Mass: 605.6 mg (1.54 mmol)

NMR

Indicates more side product than desired product, but uncertain.

KBS17-4 cr_1.zip

KBS17-4 cr processed.pdf

[KlementineJBS]

26.07.22

LRMS

KBS17-4 cr.d.zip

KBS17-4 cr.pdf

[KlementineJBS]

26.07.22

Ran a manual column - filled with silica slurry (in pet. benz.) to give about ~10 cm silica in a 2.5 cm diameter column.

Loaded sample (in pet. benz.) and added fine layer of sand. Added solvent mixture via pipette on sides of column.

Solvent system

100 mL 5:95 EtOAc:pet. benz. 100 mL 10:90 EtOAc:pet. benz. 100 mL 20:80 EtOAc:pet. benz. 50 mL 30:70 EtOAc:pet. benz.

Collected ~15 mL fractions.

Label	Fractions	Vial weight (g)	Vial weight (full)	Mass (mg)	Moles (mmol)	% Yield	Substance
A	1 - 5	-	-	-	-	-	-
B	6 - 15	15.9633	16.0927	129.4	0.330	26	bis-propargylated product
C	16	-	-	-	-	-	-
D	17 - 20	15.9569	16.1207	163.8	0.462	36	mono-propargylated product
E	21 - 22	15.7767	15.8075	30.8	0.097	8	starting material

NMR

B - fractions 6 - 15

1H NMR (300 MHz, CDCl3) δ 4.01 (4H), 3.29 (4H), 2.17 (2H), 1.55 (4H), 1.46 (18H), 1.30 (4H).

KBS17-4 B (F6-15)_1.zip KBS17-4 bis product.pdf

Appears to be reasonably pure desired (bis) product - minor solvent impurities.

D - fractions 17 - 20

1H NMR (300 MHz, CDCl3) δ 4.53, 4.01, 3.29, 3.10, 3.08, 2.18, 1.55, 1.46, 1.43, 1.32.

KBS17-4 D (17-20)_1.zip KBS17-4 mono product.pdf

Appears to be reasonably pure mono product - minor solvent impurities, particularly ethyl acetate.

[KlementineJBS]

KBS17-4 D (F6-15).pdf KBS17-4 D (F17-20).pdf KBS17-4 D (F17-20).d.zip KBS17-4 B (F6-15).d.zip